List of phenyltropanes explained

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.[1]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article) Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

2-Carboxymethyl esters (phenyl-methylecgonines)

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.[2]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.

Blank spacings within tables for omitted data use "no data", "?", "-" or "" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)! Structure ! Short Name
i.e. Trivial IUPAC
(non-systematic) Name
(Singh's #)! R (para-substitution)
of benzene! DA
[<sup>3</sup>H]WIN 35428
IC50 nM
(Ki nM)! 5HT
[<sup>3</sup>H]paroxetine
IC50 nM
(Ki nM)! NE
[<sup>3</sup>H]nisoxetine
IC50 nM
(Ki nM)! selectivity
5-HTT/DAT! selectivity
NET/DAT
cocaine
(benzoyloxytropane)
H 102 ± 12
241 ± 18ɑ
1045 ± 89
112 ± 2b
3298 ± 293
160 ± 15c
10.2
0.5d
32.3
0.7e
(para-hydrogen)phenyltropane
WIN 35,065-2 (β-CPT) Troparil
11a
H 23 ± 5.0
49.8 ± 2.2ɑ
1962 ± 61
173 ± 13b
920 ± 73
37.2 ± 5.2c
85.3
3.5d
40.0
0.7e
para-fluorophenyltropane
WIN 35,428 (β-CFT)
11b
14 (15.7 ± 1.4)
22.9 ± 0.4ɑ
156 (810 ± 59)
100 ± 13b
85 (835 ± 45)
38.6 ± 9.9c
51.6
4.4d
53.2
1.7e
para-nitrophenyltropane
11k
NO210.1 ± 0.10????
para-aminophenyltropane
RTI-29[3]
11j
NH29.8
24.8 ± 1.3g
5110151521.415.4
para-chlorophenyltropane
RTI-31
11c
1.12 ± 0.06
3.68 ± 0.09ɑ
44.5 ± 1.3
5.00 ± 0.05b
37 ± 2.1
5.86 ± 0.67c
39.7
1.3d
33.0
1.7e
para-methylphenyltropane
RTI-32 Tolpane
11f
1.71 ± 0.30
7.02 ± 0.30ɑ
240 ± 27
19.38 ± 0.65b
60 ± 0.53e
8.42 ± 1.53c
140
2.8d
35.1
1.2e
para-bromophenyltropane
RTI-51 Bromopane
11d
1.81 (1.69) ± 0.30 10.6 ± 0.2437.4 ± 5.25.820.7
para-iodophenyltropane
RTI-55 (β-CIT) Iometopane
11e
I1.26 ± 0.04
1.96 ± 0.09ɑ
4.21 ± 0.3
1.74 ± 0.23b
36 ± 2.7
7.51 ± 0.82c
3.3
0.9d
28.6
3.8e
para-hydroxyphenyltropane
11h
OH12.1 ± 0.86
para-methoxyphenyltropane
11i
OCH38.14 ± 1.3
para-azidophenyltropane
11l
N32.12 ± 0.13
para-trifluoromethylphenyltropane
11m
CF313.1 ± 2.2
para-acetylaminophenyltropane
11n
NHCOCH364.2 ± 2.6
para-propionylaminophenyltropane
11o
NHCOC2H5121 ± 2.7
para-ethoxycarbonylaminophenyltropane
11p
NHCO2C3H5316 ± 48
para-trimethylstannylphenyltropane
11q
Sn(CH3)3144 ± 37
para-ethylphenyltropane
RTI-83
11g
Et55 ± 2.128.4 ± 3.8
(2.58 ± 3.5)
4030 (3910) ± 381
(2360 ± 230)
0.573.3
para-n-propylphenyltropane
RTI-282i
11r
n-C3H768.5 ± 7.170.4 ± 4.13920 ± 1301.057.2
para-isopropylphenyltropane
11s
CH(CH3)2597 ± 52191 ± 9.575000 ± 58200.3126
para-vinylphenyltropane
RTI-359
11t
CH-CH21.24 ± 0.29.5 ± 0.878 ± 4.17.762.9
para-methylethenylphenyltropane
RTI-283j
11u
C(=CH2)CH314.4 ± 0.33.13 ± 0.161330 ± 3330.292.4
para-trans-propenylphenyltropane
RTI-296i
11v
trans-CH=CHCH35.29 ± 0.5311.4 ± 0.281590 ± 932.1300
para-allylphenyltropane
11x
CH2CH=CH232.8 ± 3.128.4 ± 2.42480 ± 2290.975.6
para-ethynylphenyltropane
RTI-360
11y
C≡CH1.2 ± 0.14.4 ± 0.483.2 ± 2.83.769.3
para-propynylphenyltropane
RTI-281i
11z
C≡CCH32.37 ± 0.215.7 ± 1.5820 ± 466.6346
para-cis-propenylphenyltropane
RTI-304
11w
cis-CH=CHCH315 ± 1.27.1 ± 0.712,800k ± 3000.5186.6k
para-(Z)-phenylethenylphenyltropanecis-CH=CHPh11.7 ± 1.12
para-benzylphenyltropane-CH2-Ph526 ± 657,240 ± 390
(658 ± 35)
6670 ± 377
(606 ± 277)
13.712.6
para-phenylethenylphenyltropaneCH2

-C-Ph||474 ± 133||2,710 ± 800
(246 ± 73)||7,060 ± 1,760
(4,260 ± 1,060)||5.7||14.8|-|||para-phenylethylphenyltropanel||-(CH2)2-Ph||5.14 ± 0.63||234 ± 26
(21.3 ± 2.4)||10.8 ± 0.3
(6.50 ± 0.20)||45.5||2.1|-|||para-(E)-phenylethenylphenyltropanel
RTI-436||trans–CH=CHPh||3.09 ± 0.75||335 ± 150
(30.5 ± 13.6)||1960 ± 383
(1180 ± 231)||108.4||634.3|-|||para-phenylpropylphenyltropanel||-(CH2)3-Ph||351 ± 52||1,243 ± 381
(113 ± 35)||14,200 ± 1,800
(8,500 ± 1,100)||3.5||40.4|-|||para-phenylpropenylphenyltropanel||-CH=CH-CH2-Ph||15.8 ± 1.31||781 ± 258
(71 ± 24)||1,250 ± 100
(759 ± 60)||49.4||79.1|-|||para-phenylbutylphenyltropanel||-(CH2)4-Ph||228 ± 21||4,824 ± 170
(439 ± 16)||2,310 ± 293
(1,390 ± 177)||21.1||10.1|-| ||para-phenylethynylphenyltropanel
RTI-298[4] ||–≡–Ph||3.7 ± 0.16||46.8 ± 5.8
(4.3 ± 0.53)||347 ± 25
(209 ± 15)||12.6||93.7|-| ||para-phenylpropynylphenyltropanel[5] ||–C≡C-CH2Ph||1.82 ± 0.42||13.1 ± 1.7
(1.19 ± 0.42)||27.4 ± 2.6
(16.5 ± 1.6)||7.1||15|-| ||para-phenylbutynylphenyltropanel
RTI-430||–C≡C(CH2)2Ph||6.28 ± 1.25||2180 ± 345
(198 ± 31)||1470 ± 109
(885 ± 66)||347.1||234|-| ||para-phenylpentynylphenyltropanel||–C≡C-(CH2)3-Ph||300 ± 37||1,340 ± 232
(122 ± 21)||4,450 ± 637
(2,680 ± 384)||4.46||14.8|-| ||para-trimethylsilylethynylphenyltropane||—||—||—||—||—||—|-| ||para-hydroxypropynylphenyltropane||—||—||—||—||—||—|-| ||para-hydroxyhexynylphenyltropanel||–C≡C-(CH2)4OH||57 ± 4||828 ± 29
(75 ± 2.6)||9,500 ± 812
(5,720 ± 489)||14.5||166.6|-| ||para-(thiophen-3-yl)phenyltropane
Tamagnan||p-thiophene||12||0.017||189||0.001416||15.7|-| ||para-biphenyltropane
11aa||Ph||10.3 ± 2.6f
29.4 ± 3.8ɑ
15.6 ± 0.6||95.8 ± 36
(8.7 ± 3.3)||1,480 ± 269
(892 ± 162)||6.1||94.8|-| ||3β-2-naphthyltropane
RTI-318
11bb||3β-2-naphthyl||0.51 ± 0.03
3.32 ± 0.08f
3.53 ± 0.09ɑ||0.80 ± 0.06
(0.07 ± 0.1)||21.1 ± 1.0
(12.7 ± 0.60)||1.5||41.3|-| ||para-bimethoxyphenyltropane
15||OCH2OCH3h||—||—||—||—||—|}
  • ɑ[<sup>3</sup>H]DA uptake displacement Ki value.
  • b[<sup>3</sup>H]5-HT uptake displacement Ki value.
  • c[<sup>3</sup>H]NE uptake displacement Ki value.
  • d[<sup>3</sup>H]5-HT uptake to [<sup>3</sup>H]DA uptake ratio.
  • e[<sup>3</sup>H]NE uptake to [<sup>3</sup>H]DA uptake ratio.
  • fIC50 for displacement of [<sup>3</sup>H]cocaine.
  • gValues from alternate data-set differing from that used in rest of table.
  • hOriginal source (Scheme 4, page 931, 7th of article) name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"
  • iProtonated as the (-)—tartrate salt (isomer)
  • jProtonated as the tartrate salt
  • kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1[6] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value.
  • lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the para area of the aryl of these type of ligands.

(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes

Tamagnan (thiophene) analogues of para-phenyltropanes.! Compound structure! Alphanumeric code
(name)! para-substitution! N8! SERT! DAT! NET! Selectivity
SERT versus DAT! Selectivity
SERT versus NET
1
(cocaine)
(—)-Cocaine CH3 10508933200.083.2
2
(β-CIT), (Iometopane)
Iodo CH3 0.46 ± 0.060.96 ± 0.152.80 ± 0.402.16.1
(R,S-Citalopram) 1.6016,5406,19010,3383,869
4a 2-Thiophene CH3 0.15 ± 0.01552 ± 12.8158 ± 123461,053
4b
(Tamagnan)
3-Thiophene CH3 0.017 ± 0.00412.1 ± 3189 ± 8271011,118
4c 2-(5-Br)-Thiophene CH3 0.38 ± 0.0086.43 ± 0.9324 ± 1917853
4d 2-(5-Cl)-Thiophene CH3 0.64 ± 0.044.42 ± 1.64311 ± 256.9486
4e 2-(5-I)-Thiophene CH3 4.56 ± 0.8422.1 ± 3.21,137 ± 1234.9249
4f 2-(5-NH2)-Thiophene CH3 64.7 ± 3.7>10,000>30,000>155>464
4g 2-(4,5-NO2)-Thiophene CH3 5,000>30,000>10,000>6.0>2.0
4h 3-(4-Br)-Thiophene CH3 4.02 ± 0.34183 ± 69>10,00046>2,488
5a 2-Thiophene H 0.11 ± 0.00612.2 ± 0.975.3 ± 9.6111685
5b 3-Thiophene H 0.23 ± 0.026.4 ± 0.2739 ± 0.828170

(3′,4′-Disubstituted phenyl)-tropanes

Compound
(+ S. Singh's name)
X
(4′-para)
Y
(3′-meta)
2 Position config 8 DA 5-HT NE
RTI-318
11bb
β-naphthylCO2Me β,β NMe 0.50.8120
Dichloropane (RTI-111ɑ)
17c
ClCl CO2Me β,β NMe 0.793.1318.0
RTI-88 [recheck]
17e
NH2ICO2Me β,β NMe 1.351329c320c
RTI-97
17d
NH2BrCO2Me β,β NMe 3.91181282
RTI-112b
17b
ClMeCO2Me β,β NMe 0.8210.536.2
RTI-96
17a
FMeCO2Me β,β NMe 2.9576520
EtICO2Me β,β NMe 21.32.961349
RTI-353 (EINT)EtICO2Me β,β NH 3310.69148
MeICO2Me β,β NH 5.981.0674.3
MeICO2Me β,β NMe 3.126.81484
Meltzer[7] catecholCO2Me β,β NMe >100??
MeltzerOAcOAcCO2Me β,β NMe ???
  • ɑas ·HCl (salt)
  • bas ·HCl·2 H2O (salt)
  • cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT
Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes! Compound ! Short Name
(S. Singh)! R2! R1! DA! 5HT! NE! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
meta-fluorophenyltropane
16a
F H 23 ± 7.8----
meta-chlorophenyltropane
16b
Cl H 10.6 ± 1.8----
meta-bromophenyltropane
16c
Br H 7.93 ± 0.08ɑ----
meta-iodophenyltropane
16d
I H 26.1 ± 1.7----
meta-tributylstannylphenyltropane
16e
SnBu3H 1100 ± 170----
meta-ethynylphenyltropaneC≡CHH-----
meta-methyl-para-fluorophenyltropane
RTI-96
17a
CH3 F 2.95 ± 0.58----
meta-methyl-para-chlorophenyltropane
RTI-112c
17b
CH3 Cl 0.81 ± 0.0510.5 ± 0.0536.2 ± 1.013.044.7
meta-para-dichlorophenyltropane
RTI-111b[8] Dichloropane
17c
Cl Cl 0.79 ± 0.08b3.13 ± 0.36b18.0 ± 0.8
17.96 ± 0.85b'd
4.0b22.8b
meta-bromo-para-aminophenyltropane
RTI-97
17d
Br NH2 3.91 ± 0.5918128246.272.1
meta-iodo-para-aminophenyltropane
RTI-88
17e
I NH2 1.35 ± 0.11120 ± 41329 ± 12488.9984
meta-iodo-para-azidophenyltropane
17f
I N3 4.93 ± 0.32----
3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes[9] ! Structure ! Compound! R! X! n! Inhibition of [<sup>3</sup>H]WIN 35,428
@ DAT
IC50 (nM)! Inhibition of [<sup>3</sup>H]Paroxetine
@ 5-HTT
Ki (nM)! Inhibition of [<sup>3</sup>H]Nisoxetine
@ NET
Ki (nM)! NET/DAT
(uptake ratio)! NET/5-HTT
(uptake ratio)
CocaineDes-thio/sulfinyl/sulfonyl
H
HDesmethyl
0
89.19519902221
para-methoxyphenyltropane
Singh: 11i
Des-thio/sulfinyl/sulfonyl
OCH3
H06.5 ± 1.34.3 ± 0.51110 ± 64171258
7a CH3 H 0 9 ± 30.7 ± 0.2220 ± 1024314
7b C2H5 H 0 232 ± 344.5 ± 0.51170 ± 3005260
7c CH(CH3)2 H 0 16 ± 223 ± 2129 ± 287
7d CF3 H 0 200 ± 708 ± 21900 ± 30010238
7e CH3 Br 0 10.1 ± 10.6 ± 0.2121 ± 1212202
7f CH3 Br 1 76 ± 183.2 ± 0.4690 ± 809216
7g CH3 H 1 91 ± 164.3 ± 0.6515 ± 606120
7h CH3 H 2 >10,000208 ± 45>10,000148

(2′,4′-Disubstituted phenyl)-tropanes

Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)! Compound structure
! Trivial IUPAC
(non-systematic)
Name! R2
ortho! R1
para! DA! 5HT! NE! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
ortho,para-dinitrophenyltropane[10] NO2 NO2 -----

(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes[11]
Para-methoxy/(ethoxy)-meta-substituted phenyltropanes! Structure
! Short Name
(All compounds tested as HCl salts)! R2
3′-(meta)! R3
5′-(di-meta)! OR1
4′-(para)! DAT
IC50
[3H](compound #)12! 5-HTT
Ki
[3H]Paroxetine! NET
Ki
[3H]Nisoxetine! Selectivity
NET/DAT
Ratio
Ki/IC50! Selectivity
NET/5-HTT
Ratio
Ki/Ki|-| || Cocaine||-||-||-||89.1||95||1990||22||21|-| || 6
RTI-112||-||-||-||0.82 ± 0.05||0.95 ± 0.04||21.8 ± 0.6||27||23|-| || 7a
11i || H || H ||CH3||6.5 ± 1.3||4.3 ± 0.5||1110 ± 64||171||258|-| || 7b || H || H || C2H5 ||92 ± 8||1.7 ± 0.4||1690 ± 50||18||994|-| || 7c || F || H || CH3 ||16 ± 1||4.8 ± 0.5||270 ± 50||17||56|-| || 7d || Br || H || CH3 ||47 ± 15||3.1 ± 0.1||160 ± 20||3||52|-| || 7f || Br || Br || CH3 ||92 ± 22||2.9 ± 0.1||4100 ± 400ɑ||45||1413|-| || 7e || I || H || CH3 ||170 ± 60||3.5 ± 0.4||180 ± 20||1||51|-| || 7g || I || I || CH3 ||1300 ± 200||7.5 ± 0.8||180 ± 20||4||667|}ɑN=2

(2′,4′,5′-Trisubstituted phenyl)-tropanes

Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes! Structure! Short Name! R1
2′-(ortho)! R2
4′-(para)! R3
5′-(meta)! DAT! 5-HTT! NET! Selectivity
NET/DAT
Ratio! Selectivity
NET/5-HTT
Ratio
para-ethyl-ortho, meta-diiodophenyltropane iodoethyliodo-----

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of p-methoxy-phenyltropanes

Para-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues[12] ! Structure
! Short Name
(All compounds tested as HCl salts)! CO2R (2β-substituted)
(compound 9 is 2β=R)! DAT
IC50
[3H](compound #)12! 5-HTT
Ki
[3H]Paroxetine! NET
Ki
[3H]Nisoxetine! Selectivity
NET/DAT
Ratio
Ki/IC50! Selectivity
NET/5-HTT
Ratio
Ki/Ki|-| || 7a
11i ||CH3||6.5 ± 1.3||4.3 ± 0.5||1110 ± 64||171||258|-| || 8a ||(CH3)2CH||14 ± 3||135 ± 35||2010 ± 200||144||15|-| || 8b ||cyclopropane||6.0 ± 2||29 ± 3||1230 ± 140||205||42|-| || 8c ||cyclobutane||13 ± 3||100 ± 8|| >3000 ||231||30|-| || 8d ||O2N...1,4-xylene...(CH2)2||42 ± 8||2.9 ± 0.2||330 ± 20||8||114|-| || 8e ||H2N...1,4-xylene...(CH2)2||7.0 ± 2||8.3 ± 0.4||2200 ± 300ɑ||314||265|-| || 8f ||CH3CONH...1,4-xylene...(CH2)2||6.0 ± 1||5.5 ± 0.5||1460 ± 30||243||265|-| || 8g ||H2N...2-bromo-1,4-dimethylbenzene...(CH2)2||3.3 ± 1.4||4.1 ± 0.6||1850 ± 90||561||451|-| || 8h ||H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)2||15 ± 6||2.0 ± 0.4||2710 ± 250ɑ||181||1360|-| || 8i ||H2N...2-iodo-1,4-dimethylbenzene...(CH2)2||2.5 ± 0.7||3.5 ± 1||2040 ± 300ɑ||816||583|-| || 8j ||H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2||102 ± 15||1.0 ± 0.1||2600 ± 200ɑ||25||2600|-| || 9 ||3-(4-methylphenyl)-1,2-oxazole||18 ± 6||860 ± 170||>3000||167||3|}ɑN=2

2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes

Multi-substituted structures of 2β-ester-3β-phenyltropanes! Compound
! Short Name
(S. Singh)! R! X! IC50 (nM)
DAT
[<sup>3</sup>H]WIN 35428! IC50 (nM)
5-HTT
[<sup>3</sup>H]paroxetine! IC50 (nM)
NET
[<sup>3</sup>H]nisoxetine! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
23a CH(CH3)2 H 85.1 ± 2.523121 ± 397632047 ± 1491272 376
23b C6H5 H 76.7 ± 3.6106149 ± 725619262 ± 5931384 251
24a CH(CH3)2 Cl 1.4 ± 0.13
6.04 ± 0.31ɑ
1400 ± 7
128 ± 15b
778 ± 21
250 ± 0.9c
1000
21.2d
556
41.4e
24b cyclopropyl Cl 0.96 ± 0.10168 ± 1.8235 ± 8.39175 245
24c C6H5 Cl 1.99 ± 0.05
5.25 ± 0.76ɑ
2340 ± 27
390 ± 34b
2960 ± 220
242 ± 30c
1176
74.3d
1.3
41.6e
24d C6H4-4-I Cl 32.6 ± 3.91227 ± 176967.6 ± 26.337.6 29.7
24e C6H4-3-CH3 Cl 9.37 ± 0.522153 ± 1432744 ± 140230 293
24f C6H4-4-CH3 Cl 27.4 ± 1.51203 ± 421277 ± 11843.9 46.6
24g C6H4-2-CH3 Cl 3.91 ± 0.233772 ± 3844783 ± 387965 1223
24h C6H4-4-Cl Cl 55 ± 2.316914 ± 10564883 ± 288307 88.8
24i C6H4-4-OCH3 Cl 71 ± 5.619689 ± 18431522 ± 94277 21.4
24j (CH2)2C6H4-4-NO2 Cl 2.71 ± 0.13- - - -
24k (CH)2C6H4-4-NH2 Cl 2.16 ± 0.25- - - -
24l (CH2)2C6H3-3-I-4-NH2 Cl 2.51 ± 0.25- - - -
24m (CH2)2C6H3-3-I-4-N3 Cl 14.5 ± 0.94- - - -
24n (CH2)2C6H4-4-N3 Cl 6.17 ± 0.57- - - -
24o (CH2)2C6H4-4-NCS Cl 5.3 ± 0.6- - - -
24p (CH2)2C6H4-4-NHCOCH2Br Cl 1.73 ± 0.06- - - -
25a CH(CH3)2 I 0.43 ± 0.05
2.79 ± 0.13ɑ
66.8 ± 6.53
12.5 ± 1.0b
285 ± 7.6
41.2 ± 3.0c
155
4.5d
663
14.8e
25b cyclopropyl I 0.61 ± 0.0815.5 ± 0.72102 ± 1125.4 167
25c C6H5 I 1.51 ± 0.34
6.85 ± 0.93ɑ
184 ± 22
51.6 ± 6.2b
3791 ± 149
32.7 ± 4.4c
122
7.5d
2510
4.8e
26a CH(CH3)2 CH3 6.45 ± 0.85
15.3 ± 2.08ɑ
6090 ± 488
917 ± 54b
1926 ± 38
73.4 ± 11.6c
944
59.9d
299
4.8e
26b CH(C2H5)2 CH3 19.1 ± 14499 ± 5573444 ± 44235 180
26c cyclopropyl CH3 17.8 ± 0.76485 ± 212628 ± 25227.2 148
26d cyclobutyl CH3 3.74 ± 0.522019 ± 1334738 ± 322540 1267
26e cyclopentyl CH3 1.68 ± 0.141066 ± 109644 ± 28634 383
26f C6H5 CH3 3.27 ± 0.06
9.13 ± 0.79ɑ
24500 ± 1526
1537 ± 101b
5830 ± 370
277 ± 23c
7492
168d
1783
30.3e
26g C6H4-3-CH3 CH3 8.19 ± 0.905237 ± 4532136 ± 208639 261
26h C6H4-4-CH3 CH3 81.2 ± 1615954 ± 6144096 ± 121196 50.4
26i C6H4-2-CH3 CH3 23.2 ± 0.9711040 ± 50425695 ± 1394476 1107
26j C6H4-4-Cl CH3 117 ± 7.942761 ± 23999519 ± 864365 81.3
26k C6H4-4-OCH3 CH3 95.6 ± 8.882316 ± 78523151 ± 282861 33.0
  • ɑKi value for displacement of [<sup>3</sup>H]DA uptake.
  • bKi value for displacement of [<sup>3</sup>H]5-HT uptake.
  • cKi value for displacement of [<sup>3</sup>H]NE uptake.
  • d[<sup>3</sup>H]5-HT uptake to [<sup>3</sup>H]DA uptake ratio.
  • e[<sup>3</sup>H]NE uptake to [<sup>3</sup>H]DA uptake ratio.

Carboxyaryl

CompoundX2 Positionconfig8DA 5-HT NE
I -CO2Phβ,β NMe1.501843,791
Cl -CO2Ph β,β NMe 1.982,3362,955
NO2 -CO2Ph β,β NMe 5.942,9105,695
RTI-120 [recheck] Me -CO2Ph β,β NMe 3.2624,4715,833
Cl -CO2(p-C6H4I)β,β NMe 33 1,227 968
Cl CO2(m-C6H4Me)β,β NMe 9.3721532744
Cl -CO2(o-C6H4Me)β,β NMe 3.913,7724,783
Me -CO2(m-C6H4Me)β,β NMe 8.195,2372,137
RTI-206Cl-CO2(p-C6H4Me)β,β NMe 27.41,2031,278

2-Phenyl-3-Phenyltropanes

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake! Compound Structure! Short Name
(S. Singh)! Stereochemistry! X
(para)! DAT
[<sup>3</sup>H]WIN 35428 IC50 (nM)! DAT
[<sup>3</sup>H]Mazindol Ki (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine IC50 (nM)! [<sup>3</sup>H]DA uptake Ki (nM)! [<sup>3</sup>H]5-HT uptake Ki (nM)! Selectivity
[<sup>3</sup>H]5-HT/[<sup>3</sup>H]DA
Cocaine (2β,3β) (H) 89 ± 4.82811050 ± 894231550.4
67a 2β,3β H 12.6 ± 1.814.921000 ± 332028.9110038.1
67b 2β,3α H - 13.8-11.775364.3
67c 2α,3α H 690 ± 37-41300 ± 5300---
68 2β,3α F -6.00-4.5812226.6
69a 2β,3β CH3 1.96 ± 0.082.5811000 ± 832.8773.825.7
69b 2β,3α CH3 -2.87-4.1628769.0
69c 2α,3α CH3 429 ± 59-15800 ± 3740---

Carboxyalkyl

CodeX2 Positionconfig8DA 5-HT NE
RTI-77ClCH2C2(3-iodo-p-anilino)β,βNMe2.512247
RTI-121 IPCIT I -CO2Priβ,β NMe0.4366.8285
I -CO2Priβ,β NH1.063.59132
I -CO2Prcycβ,β NMe0.6115.5102
Cl -CO2Priβ,β NMe 1.401,404778
NO2 -CO2Pri β,β NMe 8.142,1474,095
Cl -CO2Prcycβ,β NMe 0.96168235
Me -CO2Prcycβ,β NMe1.681,066644
Me -CO2Priβ,β NMe6.456,0901,926
Me -CO2Bucycβ,β NMe3.742,0204,738
Me -CO2C(H)Et2β,β NMe1945003444
RTI-338ethyl-CO2C2Phβ,β NMe11047.413366
Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.

2-Alkyl Esters & Ethers

Esters (2-Alkyl)
2β-Alkyl Ester Phenyltropanes! Structure! Short Name
(S. Singh)! 2β=R! Ki (nM)
DAT
[<sup>3</sup>H]WIN 35428! IC50 (nM)
[<sup>3</sup>H]DA uptake! Selectivity
uptake/binding
59a CH=CHCO2CH3 22 ± 2123 ± 655.6
59b CH2CH2CO2CH3 23 ± 2166 ± 687.2
59c (CH2)2CH=CHCO2CH3 20 ± 2203 ± 7710.1
59d (CH22)4CO2CH3 30 ± 2130 ± 74.3
59e CH=CHCH2OH 26 ± 3159 ± 436.1
59f CH2CH2CH2OH 11 ± 164 ± 325.8
59g CH2CH2COC6H5 28 ± 247 ± 151.7
Ethers (2-Alkyl)

See the N-desmethyl Paroxetine homologues

2-Alkyl Ether Phenyltropanes! Molecular Structure! Short Name
(S. Singh)! Stereochemistry! DAT
[<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine IC50 (nM)! NET
[<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
Paroxetine 623 ± 250.28 ± 0.02535 ± 150.00040.8
R-60a 2β,3β 308 ± 20294 ± 185300 ± 4500.917.2
R-60b 2α,3β 172 ± 8.852.9 ± 3.626600 ± 12000.3155
R-60c 2β,3α 3.01 ± 0.242.2 ± 16123 ± 9.514.140.9
S-60d 2β,3β 1050 ± 4588.1 ± 2.827600 ± 11000.0826.3
S-60e 2α,3β 1500 ± 74447 ± 472916 ± 19500.31.9
S-60f 2β,3α 298 ± 17178 ± 1312400 ± 7200.641.6

Carboxamides

Structure Code
(S. Singh #)
X2 Positionconfig8DA
[<sup>3</sup>H]WIN 35428 (IC50 nM)
NE
[<sup>3</sup>H]nisoxetine
5-HT
[<sup>3</sup>H]paroxetine (IC50 nM)
Selectivity
5-HTT/DAT
Selectivity
NET/DAT
RTI-106
27b
ClCON(H)Meβ,β NMe 12.4 ± 1.171584 ± 621313 ± 46106128
RTI-118
27a
ClCONH2β,β NMe11.5 ± 1.64270 ± 3591621 ± 110141371
RTI-222
29d
Memorpholinylβ,β NMe11.7 ± 0.8723601 ± 1156>100K>85472017
RTI-129
27e
ClCONMe2β,β NMe 1.38 ± 0.1942 ± 481079 ± 102792683
RTI-146
27d
Cl CONHCH2OHβ,β NMe 2.05 ± 0.23144 ± 397.8 ± 1047.770.2
RTI-147
27i
Cl CON(CH2)4β,β NMe 1.38 ± 0.033,950 ± 7212400 ± 120789852862
ClCON(CH2)5β,β NMe 6.6158323468
ClCON(H)CH2C≡CHβ,β NMe16.518394827
ClCON(H)NH2β,β NMe 44.139143815
ClCONHCOMeβ,β NMe 158>43K>125K
ClCONHCH2COPhβ,β NMe 7.791722827
RTI-183
27 g
ClCON(OMe)Meβ,β NMe 0.85 ± 0.06549 ± 18.5724 ± 94852646
RTI-186
29c
MeCON(OMe)Meβ,β NMe 2.55 ± 0.43422 ± 263402 ± 3531334165
RTI-198
27h
ClCON(CH2)3β,β NMe 6.57 ± 0.67990 ± 4.8814 ± 57124151
RTI-196
27c
ClCONHOMeβ,β NMe 10.7 ± 1.259907 ± 63243700 ± 19604084926
ClCONHNHCOPhβ,β NMe 91.8>20K>48K
RTI-208
27j
ClCONO(CH2)3β,β NMe 1.47 ± 0.131083 ± 762470 ± 561680737
RTI-214
27l
Cl CON(-CH2CH2-)2Oβ,β NMe 2.90 ± 0.38545 ± 20688769 ± 1855306102946
RTI-215
27f
ClCONEt2β,β NMe 5.48 ± 0.195532 ± 2999433 ± 77017211009
ClCONH(m-C6H4OH)β,β NMe 4.78>30K>16K
RTI-218 Cl CON(Me)OMeβ,β NMe 1.195201911
RTI-226
27 m
ClCONMePhβ,β NMe 45.5 ± 32202 ± 49523610 ± 212851948.4
ICONO(CH2)3β,β NMe 0.75446230
RTI-229[13]
28a
I CON(CH2)4β,β NMe 0.37 ± 0.04991 ± 211728 ± 3946702678
27k6.95 ± 1.211752 ± 2023470 ± 226499252
28b1.08 ± 0.15103 ± 6.273.9 ± 8.168.495.4
28c0.75 ± 0.02357 ± 42130 ± 15.8173476
29a41.8 ± 2.454398 ± 2716371 ± 374152105
29b24.7 ± 1.936222 ± 72933928 ± 21921374252
✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.
2β-Carboxamide-3β-Phenyltropanes! Compound! Short Name
(S. Singh)! R! X! IC50 (nM)
DAT
[<sup>3</sup>H]WIN 35428! IC50 (nM)
5-HTT
[<sup>3</sup>H]Paroxetine! IC50 (nM)
NET
[<sup>3</sup>H]Nisoxetine! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
29a NH2 CH3 41.8 ± 2.456371 ± 3744398 ± 271152 105
29b N(CH2CH3)2 CH3 24.7 ± 1.9333928 ± 21926222 ± 7291374 252
N(OCH3)CH3 CH3 2.55 ± 0.433402 ± 353422 ± 261334 165
29d
RTI-222
4-morpholine CH3 11.7 ± 0.87>100000 23601 ± 1156>8547 2017

Carboxamide linked phenyltropanes dimers


Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize[14] to the energetically more favorable trans configuration. This can happen to cocaine also.Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.

3-Substituted-isoxazol-5-yl

N-methylphenyltropanes with 1R β,β stereochemistry.! Code
(S.S. #)! X! R! DA! NE! 5HT
Cl 3-methylisoxazol-5-yl0.59181572
Me3-methylisoxazol-5-yl0.932543818
I 3-methylisoxazol-5-yl0.7367.936.4
RTI-177 β-CPPIT
32g
Cl3-phenylisoxazol-5-yl1.28 ± 0.18504 ± 292420 ± 136
Me3-phenylisoxazol-5-yl1.583985110
I3-phenylisoxazol-5-yl2.57868100
Hmethyl43.36208
HPh285>12K
Cl 3-ethylisoxazol-5-yl0.501203086
Cl isopropyl 1.199542318
Cl 3-(4-methylphenyl)isoxazol-5-yl4.0917145741
Cl 3-t-butyl-isoxazol-5-yl7.31632137K
Cl p-chlorophenyl6.425290>76K
Cl p-anisyl1.577625880
Cl p-fluorophenyl1.869187257
RTI-354Me3-ethylisoxazol-5-yl1.622996400
RTI-366MeR = isopropyl4.52523 (1550)42,900 (3900)
RTI-371Mep-chlorophenyl8.74>100K (60,200)>100K (9090)
RTI-386Mep-anisyl3.93756 (450)4027 (380)
RTI-387Mep-fluorophenyl6.45917 (546)>100K (9400)

3-Substituted-1,2,4-oxadiazole

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.! Structure! Code
(Singh's #)! X! R! DAT (IC50 nM)
displacement of [H3]WIN 35428! NET (IC50 nM)
[H3]nisoxetine! 5-HTT (IC50 nM)
[H3]paroxetine! Selectivity
5-HTT/DAT! Selectivity
NET/DAT|-|||ααRTI-87|| H||3-methyl-1,2,4-oxadiazole||204||36K||30K|| |||-|||βαRTI-119|| H||3-methyl-1,2,4-oxadiazole||167||7K||41K|| |||-|||αβRTI-124 || H||3-methyl-1,2,4-oxadiazole||1028||71K||33K|| |||-|||RTI-125
(32a) || Cl ||3-methyl-1,2,4-oxadiazole||4.05 ± 0.57||363 ± 36||2584 ± 800||637||89.6|-|||ββRTI-126[15]
(31) || H ||3-methyl-1,2,4-oxadiazole||100 ± 6||7876 ± 551||3824 ± 420||38.3||788|-|||RTI-130
(32c) || Cl ||3-phenyl-1,2,4-oxadiazole||1.62 ± 0.02||245 ± 13||195 ± 5||120||151|-|||RTI-141
(32d)||Cl||3-(p-anisyl)-1,2,4-oxadiazole||1.81 ± 0.19||835 ± 8||337 ± 40||186||461|-|||RTI-143
(32e)||Cl||3-(p-chlorophenyl)-1,2,4-oxadiazole||4.06 ± 0.22||40270 ± 180
(4069)||404 ± 56||99.5||9919|-|||RTI-144
(32f)||Cl||3-(p-bromophenyl)-1,2,4-oxadiazole||3.44 ± 0.36||1825 ± 170||106 ± 10||30.8||532|-|||βRTI-151
(33)|| Me ||3-phenyl-1,2,4-oxadiazole||2.33 ± 0.26||60 ± 2||1074 ± 130||459||25.7|-|||αRTI-152|| Me ||3-phenyl-1,2,4-oxadiazole||494||—||1995|| |||-|||RTI-154
(32b)||Cl||3-isopropyl-1,2,4-oxadiazole||6.00 ± 0.55||135 ± 13||3460 ± 250||577||22.5|-|||RTI-155||Cl||3-cyclopropyl-1,2,4-oxadiazole||3.41||177||4362|| |||}
N-methylphenyltropanes with 1R β,β stereochemistry.! Structure! Code! X! 2 Group! DAT (IC50 nM)
displacement of [H3]WIN 35428! NET (IC50 nM)

displacement of [H3]nisoxetine! 5-HTT (IC50 nM)

displacement of [H3]paroxetine! Selectivity
5-HTT/DAT! Selectivity
NET/DAT|-|||RTI-157||Me||tetrazole||1557||>37K||>43K|| |||-|||RTI-163 || Cl ||tetrazole||911||—||5456|| |||-|||RTI-178 || Me ||5-phenyl-oxazol-2-yl||35.4||677||1699|| |||-|||RTI-188 || Cl ||5-phenyl-1,3,4-oxadiazol-2-yl||12.6||930||3304|| |||-|||RTI-189
(32i) || Cl ||5-phenyl-oxazol-2-yl||19.7 ± 1.98||496 ± 42||1120 ± 107||56.8||25.5|-|||RTI-194 || Me ||5-methyl-1,3,4-oxadiazol-2-yl||4.45||253||4885|| |||-|||RTI-195 || Me ||5-phenyl-1,3,4-oxadiazol-2-yl||47.5||1310||>22,000|| |||-|||RTI-199 || Me ||5-phenyl-1,3,4-thiadiazol-2-yl||35.9||>24,000||>51,000|| |||-|||RTI-200 || Cl ||5-phenyl-1,3,4-thiadiazol-2-yl||15.3||4142||>18,000|| |||-|||RTI-202 || Cl ||benzothiazol-2-yl||1.37||403||1119|| |||-|||RTI-219 || Cl ||5-phenylthiazol-2-yl||5.71||8516||10,342|| |||-| ||RTI-262||Cl|| ||188.2 ± 5.01||595.25 ± 5738||5207 ± 488||316||28|-|||RTI-370 || Me ||3-(p-cresyl)isoxazol-5-yl||8.74||6980||>100K|| |||-|||RTI-371 || Cl ||3-(p-chlorophenyl)isoxazol-5-yl||13||>100K||>100K|| |||-|||RTI-436||Me||-CH=CHPh[16] ||3.09||1960 (1181)||335 (31)|| |||-|||RTI-470||Cl||o-Cl-benzothiazol-2-yl||0.094||1590 (994)||1080 (98)|| |||-|||RTI-451||Me||benzothiazol-2-yl||1.53||476 (287)||7120 (647)|| |||-|||32g|| || ||1.28 ± 0.18||504 ± 29||2420 ± 136||1891||394|-|||32h|| || ||12.6 ± 10.3||929 ± 88||330 ± 196||262||73.7|}

N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

Acyl (C2-propanoyl)


  1. (#)
XY2 Positionconfig8DA5-HTNE
WF-23
(39n)
β-naphthylC(O)Et β,β NMe 0.115 0.394 No data
WF-31 PIT -Pri HC.O.Et β,β NMe 615 54.5 No data
WF-11 PTT
(39e)
Me H-C.O.Et β,β NMe 8.2 131 No data
WF-25
(39a)
H H-C.O.Et β,β NMe 48.3 1005 No data
6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data
Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)
2β-acyl-3β-phenyltropane structures! Structure! S. Singh's
alphanumeric
assignation
(name)! R1! R2! DAT[<sup>125</sup>I]RTI-55 IC50 (nM)! 5-HTT[<sup>3</sup>H]Paroxetine Ki (nM)! Selectivity5-HTT/DAT
cocaine 173 ± 19
Troparil
11a
(WIN 35065-2)
98.8 ± 12.2
WF-25
39a
C2H5C6H548.3 ± 2.81005 ± 11220.8
39b CH3C6H5114 ± 221364 ± 61612.0
39c C2H5C6H4-4-F15.3 ± 2.8630 ± 6741.2
39d CH3C6H4-4-F70.8 ± 13857 ± 18712.1
WF-11
39e
C2H5C6H4-4-CH38.2 ± 1.6131 ± 116.0
(+)-39e C2H5C6H4-4-CH34.21 ± 0.0574 ± 1217.6
(-)-39e C2H5C6H4-4-CH31337 ± 122>10000
39f CH3C6H4-4-CH39.8 ± 0.5122 ± 2212.4
39g CH3C6H4-4-C2H5152 ± 2478.2 ± 220.5
39h C2H5C6H4-4-CH(CH3)2436 ± 4135.8 ± 4.40.08
39i C2H5C6H4-4-C(CH3)32120 ± 6301771 ± 4740.8
39j C2H5C6H4-4-C6H52.29 ± 1.084.31 ± 0.011.9
39k C2H5C6H4-2-CH31287 ± 322710000>7.8
39l C2H51-naphthyl5.43 ± 1.2720.9 ± 2.93.8
39m CH31-naphthyl10.1 ± 2.225.6 ± 5.12.5
WF-23
39n
C2H52-naphthyl0.115 ± 0.0210.394 ± 0.0743.5
39o CH32-naphthyl0.28 ± 0.111.06 ± 0.363.8
39p C2H5C6H4-4-CH(C2H5)2270 ± 38540 ± 512.0
39q C2H5C6H4-4-C6H11320 ± 5597 ± 120.30
39r C2H5C6H4-4-CH=CH20.90 ± 0.343.2 ± 1.33.5
39s C2H5C6H4-4-C(=CH2)CH37.2 ± 2.10.82 ± 0.380.1

2β-Acyl-3β-naphthyl substituted

2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes[17] ! Structure! Short Assignation
(Numeric code, Davies UB)
S. Singh! R! DAT
[<sup>125</sup>H]RTI-55ɑ
IC50 nM! SERT
[<sup>3</sup>H]paroxetineb
Ki nM! NET
[<sup>3</sup>H]nisoxetinec
Ki nM! potency ratio
SERT/DAT! potency ratio
SERT/NET|-|||WF-11
(6)||4′-Me ||8.2 ± 1.6||131 ± 10||65 ± 9.2||0.06||0.5|-|||WF-31
(7)||4′-iPr ||436 ± 41||36 ± 4||>10,000||12||>250|-|||WF-23
(8)||2-naphthalene ||0.12 ± 0.02||0.39 ± 0.07||2.9 ± 0.5||0.3||7|-|||2β-acyl-3β-1-naphthalene
(9a)||4′-H||5.3 ± 1.3||21 ± 2.9||49 ± 10||0.3||18|-|||(9b)||4′-Me||25.1 ± 0.5||8.99 ± 1.70||163 ± 36||3||18|-|||(9c)||4′-Et||75.1 ± 11.9||175 ± 25||4769 ± 688||0.7||27|-|||(9d)||4′-iPr||225 ± 36||136 ± 64||>10,000||2||>73.5|-|||(10a)||6′-Et ||0.15 ± 0.04||0.38 ± 0.19||27.7 ± 9.6||0.4||74|-|||(10b)||6′-iPr||0.39 ± 0.04||1.97 ± 0.33||no data||0.2||—|-|||(10ce)||6′- OMe||0.13 ± 0.04||2.24 ± 0.34||no data||0.05||—|-|||(10d)||5′-Et, 6′-OMe||30.8 ± 6.6||7.55 ± 1.57||3362 ± 148||4.1||445|-|||(10e)||5′-C(Me)=CH2, 6′-OMe||45.0 ± 3.7||88.0 ± 13.3||2334 ± 378||0.5||26.5|-|||(10f)||6′-I||0.35 ± 0.07||0.37 ± 0.02||no data||1.0||—|-|||(10g)||7′-I ||0.45 ± 0.05||0.47 ± 0.02||no data||0.5d||—|-|||(10h)||5′-NO2, 6′-OMe||148 ± 50||15 ± 1.6||no data||10||—|-|||(10i)||5′-I, 6′-OMe ||1.31 ± 0.33||2.27 ± 0.31||781 ± 181||0.6||344|-|||(10j)||5′-COMe, 6′-OMe||12.6 ± 3.8||15.8 ± 1.65||498 ± 24||0.8||32|-|||(11a)||2β-COCH3, 1-naphthyl||10 ± 2.2||26 ± 5.1||165 ± 40||0.4||6.3|-|||(11b)||2α-COCH3, 1-naphthyl||97 ± 21||217 ± 55||no data||0.45||—|-|||(11c)||2α-COCH2CH3, 2-naphthyl||2.51 ± 0.82||16.4 ± 2.0||68.0 ± 10.8||0.15||4.1|-|||(11d)||2β-COCH3, 2-naphthyl||1.27 ± 0.15||1.06 ± 0.36||4.9 ± 1.2||1.2||4.6|-|||(11e)||2β-COCH(CH3)2, 2-naphthyl||0.25 ± 0.08||2.08 ± 0.80||37.6 ± 10.5||0.12||18.1|-|||(11f)
79a||2β-COCH2CH3, 2-naphthyl, N8-demethyl||0.03 ± 0.01||0.23 ± 0.07||2.05 ± 0.9||0.13||8.9|}
  • ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23
    (source equates WF-23 as analogue 3a, but table gives # as analogue 8)
  • b nonspecific binding was determined in the presence of 10.0 μM fluoxetine
  • c nonspecific binding was determined in the presence of 1.0 μM desipramine
  • d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values
  • e sources differ on whether C2 position acyl is alpha or beta configured

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

CodeX2 Positionconfig8DA 5-HT NE
F -CH2OH β,β NMe 474741no data
I -CH2OH β,β NMe2.2 26 no data
Br -CH2OH β,β NMe 1.4951no data
Cl -CH2OH β,β NMe 1.5320443.8
Cl -CH2OAc β,β NMe 1.60143127
Cl -CH2OBz β,β NMe 1.783.53393
RTI-145Cl-CH2OCO2Meβ,β NMe9.602.931.48

2-Alkane/Alkene

2-Alkane/Alkene-3-Phenyltropanes! Structure! Singh's #! R! X! DAT
mazindol displacement! DA uptake! 5-HT Uptake! Selectivity
DA uptake/DAT binding
11a
WIN 35062-2
89.453.71860.6
11c 0.83 ± 00.728.5 ± 0.934.3
11f 5.766.9223.21.2
41a (CH2)2CH3 H 12.2 6.89 86.8 0.6
41b (CH2)3C6H5 H 16 ± 2a43 ± 13b2.7
42 (CH2)2CH3 F 5.28 1.99 21.7 0.4
43a CH=CH2 Cl 0.59 ± 0.15 2.47 ± 0.54.2
43b E-CH=CHCl Cl 0.42 ± 0.04 1.13 ± 0.272.7
43c Z-CH=CHCl Cl 0.22 ± 0.02 0.88 ± 0.054.0
43d E-CH=CHC6H5 Cl 0.31 ± 0.04 0.66 ± 0.01 2.1
43e Z-CH=CHC6H5 Cl 0.14 ± 0.07 0.31 ± 0.092.2
43f CH2CH3 Cl 2.17 ± 0.20 2.35 ± 0.521.1
43 g (CH2)2CH3 Cl 0.94 ± 0.08 1.08 ± 0.051.1
43h (CH2)3CH3 Cl 1.21 ± 0.180.84 ± 0.05 0.7
43i (CH2)5CH3 Cl 156 ± 15 271 ± 3 1.7
43j (CH2)2C6H5 Cl 1.43 ± 0.03 1.54 ± 0.08 1.0
44a (CH2)2CH3 CH3 1.571.1010.3 0.7
44b (CH2)3CH3 CH3 1.82 1.31 15.1 0.7
45 (CH2)2CH3 H 74.9 30.2 389 0.4
46 (CH2)2CH3 F 21.112.1 99.60.6
47a (CH2)2CH3 CH3 8.91 11.8 50.1 1.3
47b (CH2)3CH3 CH3 11.4 10.1 51.0 0.9
aKi value for displacement of WIN 35428.
bIC50 value.

Irreversible covalent (cf. ionic) C2 ligands


Irreversible (phenylisothiocyanate) binding ligand (Murthy . V.. Martin . T. J.. Kim . S.. Davies . H. M. L.. Childers . S. R.. In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain. 10.1124/jpet.108.138842. Journal of Pharmacology and Experimental Therapeutics. 326. 2. 587–595. 2008. 18492949. 5996473.)[18] RTI-76:[19] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

C2 Acyl, N8 phenylisothiocyanate


HD-205 (Murthy et al., 2007)[20]

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes


2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-[3-(Diarylmethoxy)propyl]-3β-aryltropanes.[21] [22] ! Structure! Compound! R! X! Y! [<sup>3</sup>H]WIN 35,428
@ DAT
Ki (nM)! [<sup>3</sup>H]Citalopram
@ SERT
Ki (nM)! [<sup>3</sup>H]Nisoxetine
@ NET
Ki (nM)! [<sup>3</sup>H]Pirenzepine
@ M1
Ki (nM)|-|rowspan=10||-| 9a ||CH3||H||H||34 ± 2||121 ± 19||684 ± 100||10,600 ± 1,100|-| 9b ||F||H||H||49 ± 12||—||—||—|-| 9c ||Cl||H||H||52 ± 2.1||147 ± 8||1,190 ± 72||11,000 ± 1,290|-| 9d ||CH3||Cl||H||80 ± 9||443 ± 60||4,400 ± 238||31,600 ± 4,300|-| 9e ||F||Cl||H||112 ± 11||—||—||—|-| 9f ||Cl||Cl||H||76 ± 7||462 ± 36||2,056 ± 236||39,900 ± 5,050|-| 9g ||CH3||F||F||62 ± 7||233 ± 24||1,830 ± 177||15,500 ± 1,400|-| 9h ||F||F||F||63 ± 13||—||—||—|-| 9i ||Cl||F||F||99 ± 18||245 ± 16||2,890 ± 222||16,300 ± 1,300|-|rowspan=7||-| 10a ||CH3||H||H||455 ± 36||530 ± 72||2,609 ± 195||12,600 ± 1,790|-| 10c ||Cl||H||H||478 ± 72||408 ± 16||3,998 ± 256||11,500 ± 1,720|-| 10d ||CH3||Cl||H||937 ± 84||1,001 ± 109||22,500 ± 2,821||18,200 ± 2,600|-| 10f ||Cl||Cl||H||553 ± 106||1,293 ± 40||5,600 ± 183||9,600 ± 600|-| 10g ||CH3||F||F||690 ± 76||786 ± 67||16,000 ± 637||9,700 ± 900|-| 10i ||Cl||F||F||250 ± 40||724 ± 100||52,300 ± 13,600||9,930 ± 1,090|-|rowspan=7||-| 12a ||H||H||H||139 ± 15||61 ± 9||207 ± 30||7,970 ± 631|-| 12b ||H||Cl||H||261 ± 19||45 ± 3||—||24,600 ± 2,930|-| 12c ||H||F||F||60 ± 7||—||—||—|}

F&B series (Biotin side-chains etc.)

One patent claims a series of compounds with biotin-related sidechains are pesticides.

StructureCodepara-XC2-Tropane PositionconfigDA NE5-HT
H F1 β,β
MeF1cβ,β 4.49155.6
MeF2β,β 4.3851673.6
MeF3dβ,β 1.7540272.4
F3β,β
MeB1dβ,β 1.6386.8138
MeB2dβ,β 7.27258363
MeB3dβ,β 15.6180933.7
ClF4cβ,β 77.3
MeF4cβ,β 50.33000
F5 β,β
ClF6cβ,β 9.7346746.96
ClF1cβ,β 8.32502381.6
MeF2β,β 4.80836842
MeF7 wrongβ,β 2.52324455
MeF7 rightβ,β 3.891014382
MeF8β,β 5.55788986

Miscellany (i.e. Misc./Miscellaneous) C2-substituents

StructureCodeX2 Positionconfig8DA 5-HT NE
RTI-102ICO2Hβ,β NMe 474192843,400
RTI-103BrCO2Hβ,β NMe 278307017,400
RTI-104FCO2Hβ,β NMe 2744>100K>100K
Cl -CH2Cl β,β NMe 2.6498129.8
Me -CH2CO2Meβ,β NMe1.02619124
Cl -CH3β,β NMe 1.678557
Cl -C≡Nβ,β NMe 13.118872516
Cl H3C–C=CH2β,β NMe 1.2857141
Cl -CHMe2β,β NMe 1.3838.484.5
RTI-145Cl -CH2OCO2Meβ,β NMe 9.602,9321,478
Me -C≡Nβ,β NMe5750951624
Me -CH2NH2β,β NMe10.5855120
Me -CH2NHMeβ,β NMe13.62246280
Me -CH2NMe2β,β NMe3.48206137
Me -CHMe2β,β NMe0.6111435.6
Et -CO2CH2Phβ,β NMe11047.413366
H -Ph β,β NMe28.2>34,0002670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)

Aryl-Tropenes

WO . 2004113297. Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. 2004-12-29. NeuroSearch AS. Peters. Dan . Olsen. Gunnar M.. Nielsen. Elsebet Oestergaard . Scheel-Krueger. Joergen.

Test compoundDA-uptake IC50(μM)NA-uptake IC50(μM)5-HT-uptake IC50(μM) - (+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene0.260.0280.010 - (+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene0.0580.0130.00034 - (–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene0.0340.0180.00023
Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene184.90.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene1.50.50.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene22.008.000.0036

Enantioselective nonstandard configurations (non-2β-,3β-)

β,α Stereochemistry

Structure Compound
(RTI #)

(S. Singh's #)
X2 Groupconfig8DAT IC50 (nM)
[<sup>3</sup>H]WIN 35428
5-HTT IC50 (nM)
[<sup>3</sup>H]paroxetine
NET IC50 (nM)
[<sup>3</sup>H]nisoxetine
selectivity
5-HTT/DAT
selectivity
NET/DAT
RTI-140
20a
H CO2Me β,α NMe 101 ± 165,701 ± 7212,076 ± 28556.420.6
RTI-352ɑ
20d
I CO2Me β,α NMe 2.86 ± 0.1664.9 ± 1.9752.4 ± 4.922.818.4
Br CO2Me β,α NMe
RTI-319b 3α-2-naphthylCO2Me β,α NMe1.1 ± 0.0911.4 ± 1.370.2 ± 6.28
RTI-286c
20b
F CO2Me β,α NMe21 ± 0.575062 ± 4851231 ± 9124158.6
RTI-274dFCH2O(3′,4′-MD-phenyl)β,α NH3.965.6214.4
Et CO2Meβ,α NMe327168717,819
20c ClCO2Meβ,αNMe2.4 ± 0.2998 ± 12060.1 ± 2.441625.0
20e MeCO2Meβ,αNMe10.2 ± 0.084250 ± 422275 ± 2441727.0
BnCO2Meβ,αNMe

α,β Stereochemistry

CA. 2112084.

CompoundDA (μM)M.E.D. (mg/kg)Dose (mg/kg)Activity Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane0.39<15000
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane0.112500
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane0.0160.2550++++

di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)

CompoundX2 Groupconfig8DA5-HTNE - Cl2 methyl aldoxime α,β NMe - Cl2 ethoxymethyl α,β NMe 65111.7 - NS-2359 (GSK-372,475)Cl2 Methoxymethyl α,β NH

fumaric acid salts (of α,β configured phenyltropanes)

WO. 2004072075. Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. 2004-08-26. NeuroSearch AS. Peters. Dan . Olsen. Gunnar M.. Nielsen. Elsebet Oestergaard . Scheel-Krueger. Joergen.

Test CompoundDA uptake IC50(μM)NE uptake IC50(μM)5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.0350.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0620.150.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.100.0480.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt0.0880.0510.013

Arene equivalent alterations

η6-3β-(transition metal complexed phenyl)tropanes

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.[23]).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.

Displacement of Receptor-Bound [<sup>3</sup>H]WIN 35428 and Inhibition of [<sup>3</sup>H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes! Structure! Compound #
(S. Singh)
Systematic name! Ki (nM)ɑ! IC50 (nM)! selectivity
binding/uptake
21ac17 ± 15b
224 ± 83
41824.6
21bd2280 ± 18338901.7
Cocaine32 ± 5
388 ±221
40512.6
Troparil (11a)33 ± 17
314 ± 222
37311.3
  • ɑThe binding data fit a two-site model better than a one-site model
  • bThe Ki value for the one-site model was 124 ± 10 nM
  • cIUPAC: [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
  • dIUPAC: [η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

3-(2-thiophene) and 3-(2-furan)

CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt0.300.00190.00052
2(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.360.00360.00042
3(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.310.000900.00036
4(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt0.920.00300.00053
5(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.0740.00180.00074
6(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt0.190.00160.00054

Diaryl

6/7-tropane position substituted

2β-carbomethoxy 6/7 substituted

6/7-Substituted 2-carbomethoxy-phenyltropanes! Structure! Compound #
(S. Singh)! Substitution! DAT (IC50 nM)
displacement of [H<sup>3</sup>]WIN 35428! 5-HTT (IC50 nM)
[H<sup>3</sup>]Citalopram! Selectivity
5-HTT/DAT
Cocaine H65 ± 12--
103a 3β,2β, 7-OMe
3′,4′-Cl2
86 ± 4.7884 ± 10010.3
103b 3β,2β, 7-OH
3′,4′-Cl2
1.42 ± 0.0328.6 ± 7.820.1
103c 3α,2β, 7-OH
3′,4′-Cl2
1.19 ± 0.161390 ± 561168
104a 3β,2β, 6-OH
4′-Me
215ɑ--
104b 3β,2α, 6-OH
4′-Me
15310ɑ--
104c 3α,2β, 6-OH
4′-Me
930ɑ--
104d 3α,2α, 6-OH
4′-Me
7860ɑ--
  • ɑIC50 value for displacement of [H<sup>3</sup>]mazindol. IC50 for cocaine 288 nM for displacement of [H<sup>3</sup>]mazindol

3-butyl 6/7 substituted

6/7-Substituted 3-butyl-phenyltropanes! Structure! Compound #
(S. Singh)! Substituent! Ki nM
displacement of [H<sup>3</sup>]mazindol binding! Ki nM
[H<sup>3</sup>]DA uptake! Selectivity
uptake/binding
Cocaine H270 ± 0.03400 ± 201.5
121a 7β-CN2020 ± 10710 ± 400.3
121b 6β-CN3040 ± 4806030 ± 8802.0
121c 7β-SO2Ph4010 ± 3108280 ± 13402.1
121d 6β-SO2Ph4450 ± 4308270 ± 6901.8
121e 7α-OH830 ± 40780 ± 600.9
121f H100 ± 1061 ± 100.6
121g 7β-CN24000 ± 342032100 ± 85401.3
121h 6β-CN11300 ± 154026600 ± 33302.3
121i 7β-SO2Ph7690 ± 27707050 ± 4500.9
121j 6β-SO2Ph4190 ± 7008590 ± 13602.0
121k 7α-SO2Ph3420 ± 1100--
121l 7β-SO2Ph, 7α-F840 ± 2602520 ± 2903.0
121m 7α-F200 ± 10680 ± 103.4
121n 7β-F500 ± 10550 ± 1401.1

intermediate 6- & 7-position synthesis modified phenyltropanes

6/7-synthetic intermediates! Structure! Compound #
(S. Singh)! Substituent W! Substituent X! Substituent Y! Substituent Z
(±)-122a CNHHH
(±)-122b HHCHH
(±)-122c HCHHH
(±)-122d HHHCH
(±)-122e SO2PhHHH
(±)-122f HHSO2PhH
(±)-122g HSO2PhHH
(±)-122h SO2PhFHH
(±)-122i FSO2PhHH
(±)-122j HHSO2PhF

8-tropane (bridgehead) position modified

Nortropanes (N-demethylated)

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.[24] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.[25]

Selected ββ Nortropanes! Code
(S.S. #)! X
para
! DA! 5HT! NE
RTI-142
75b
F4.3968.618.8
RTI-98
75d
Norɑ-RTI-55
I0.69 0.36 11.0
RTI-110
75c
Cl0.624.135.45
RTI-173
75f
Et49.98.13122
RTI-279
Norɑ-RTI-280
para-Me
meta-I
5.98 ± 0.481.06 ± 0.1074.3 ± 3.8
RTI-305
Norɑ-RTI-360/11y
Ethynyl1.24 ± 0.111.59 ± 0.221.8 ± 1.0
RTI-307
Norɑ-RTI-281/11z
Propynyl6.11 ± 0.673.16 ± 0.33115.6 ± 5.1
RTI-309
Norɑ-11t
Vinyl1.73 ± 0.052.25 ± 0.1714.9 ± 1.18
RTI-330
Norɑ-11s
Isopropyl310.2 ± 2115.1 ± 0.97
RTI-353para-Et
meta-I
330.54 ± 17.120.69 ± 0.07148.4 ± 9.15
ɑThe N-demethylated variant of (i.e. compound code-name after dash)
N-demethylating various β,β p-HC-phenyltropanes!N-Me compound code#

N-demethylated derivative
compound code #!para-X![<sup>3</sup>H]Paroxetine![<sup>3</sup>H]WIN 35,428![<sup>3</sup>H]Nisoxetine
11 g75fEthyl28.4 → 8.1355 → 49.94,029 → 122
11t75iVinyl9.5 → 2.251.24 → 1.7378 → 14.9
11y75nEthynyl4.4 → 1.591.2 → 1.2483.2 → 21.8
11r75 g1-Propyl70.4 → 2668.5 → 2123,920 → 532
11v75ktrans-propenyl11.4 → 1.35.29 → 28.61,590 → 54
11w75lcis-propenyl7.09 → 1.1515 → 31.62,800 → 147
11x75 mAllyl28.4 → 6.232.8 → 56.52,480 → 89.7
11z75o1-Propynyl15.7 → 3.162.37 → 6.11820 → 116
11s75hi-Propyl191 → 15.1597 → 31075,000 → ?
11u75j2-Propenyl3.13 → 0.614.4 → 231,330? → 144
N-Demethylating phenyltropanes to find a NRI
Isomer4′3′NEDA5HT
β,βMeH60 → 7.21.7 → 0.84240 → 135
β,βFH835 → 18.815.7 → 4.4760 → 68.6
β,βClH37 → 5.451.12 → 0.6245 → 4.13
β,αMeH270 → 910.2 → 33.64250 → 500
β,αFH1200 → 9.821 → 32.65060 → 92.4
β,αClH60 → 5.412.4 → 3.1998 → 53.3
β,αFMe148 → 4.2313.7 → 9.381161 → 69.8
β,αMeF44.7 → 0.867.38 → 91150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).[26]

N-norphenyltropanes! Structure! Short Name
(S. Singh)! Para-X! DAT
[<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine IC50 (nM)! NET
[<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
Norcocaine H206 ± 29127 ± 13139 ± 90.60.7
75a H30.8 ± 2.3156 ± 884.5 ± 7.55.12.7
75b F4.39 ± 0.2068.6 ± 2.018.8 ± 0.715.64.3
75c Cl0.62 ± 0.094.13 ± 0.625.45 ± 0.216.78.8
75d I0.69 ± 0.20.36 ± 0.057.54 ± 3.190.510.9
75e para-I
&<br />2β-CO2CH(CH3)2
1.06 ± 0.123.59 ± 0.27132 ± 53.4124
75f C2H549.9 ± 7.38.13 ± 0.30122 ± 120.22.4
75g n-C3H7212 ± 1726 ± 1.3532 ± 8.10.12.5
75h CH(CH3)2310 ± 2115.1 ± 0.97-0.05-
75i CH=CH21.73 ± 0.052.25 ± 0.1714.9 ± 1.181.38.6
75j C-CH3

CH2||23 ± 0.9||0.6 ± 0.06||144 ± 12||0.03||6.3|-| || 75k ||trans-CH=CHCH3||28.6 ± 3.1||1.3 ± 0.1||54 ± 16||0.04||1.9|-| || 75l ||cis-CH=CHCH3||31.6 ± 2.2||1.15 ± 0.1||147 ± 4.3||0.04||4.6|-| || 75m ||CH2CH=CH2||56.5 ± 56||6.2 ± 0.3||89.7 ± 9.6||0.1||1.6|-| || 75n ||CH≡CH||1.24 ± 0.11||1.59 ± 0.2||21.8 ± 1.0||1.3||17.6|-| || 75o ||CH≡CCH3||6.11 ± 0.67||3.16 ± 0.33||116 ± 5.1||0.5||19.0|-| || 75pɑ||3,4-Cl2||0.66 ± 0.24||1.4b||-||2.1||-|}ɑThese values determined in Cynomolgus monkey caudate-putamenbThe radioligand used for 5-HTT was [<sup>3</sup>H]citalopram
2β-Propanoyl-N-norphenyltropanes! Compound Structure! Short Name
(S. Singh)! DAT
[<sup>125</sup>I]RTI-55 IC50 (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine Ki (nM)! NET
[<sup>3</sup>H]Nisoxetine Ki (nM)! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
79a 0.07 ± 0.010.22 ± 0.162.0 ± 0.093.128.6
79b 4.7 ± 0.5819 ± 1.45.5 ± 2.04.01.2
79c 380 ± 1105.3 ± 1.03400 ± 2700.018.9
79d 190 ± 17150 ± 505100 ± 2200.826.8
79e 490 ± 12085 ± 164300 ± 11000.18.8
79f 1.5 ± 1.10.32 ± 0.0610.9 ± 1.50.27.3
79g 16 ± 4.90.11 ± 0.0294 ± 180.075.9

Paroxetine homologues

See the N-methyl paroxetine homologuescf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies! Compound Structure! Short Name
(S. Singh)! Stereochemistry! DAT
[<sup>3</sup>H]WIN 35428 IC50 (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine IC50 (nM)! NET
[<sup>3</sup>H]Nisoxetine IC50 (nM)! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
Paroxetine -623 ± 250.28 ± 0.02535 ± 150.00040.8
R-81a 2β,3β835 ± 90480 ± 2137400 ± 14000.644.8
R-81b 2α,3β142 ± 1390 ± 3.42500 ± 2500.617.6
R-81c 2β,3α3.86 ± 0.25.62 ± 0.214.4 ± 1.31.43.7
S-81d 2β,3β1210 ± 33424 ± 1517300 ± 18000.314.3
S-81e 2α,3β27.6 ± 2.455.8 ± 5.731690 ± 1502.061.2
S-81f 2β,3α407 ± 3319 ± 1.81990 ± 1760.054.9

N-replaced (S,O,C)

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Compound X 2 Group config 8 DA5-HTNE - Cl,ClCO2Me (racemic) β,β O 3.36.5No data - O-4210[27] p-F 3-methyl-5-isoxazole β,β S 7.0 >1000 No data

8-oxa bridgehead replacements

8-Oxanortropanes, binding inhibition using monkey caudate-putamen! Structure! Compound #
(S. Singh)! Para-
(meta-)! DAT (IC50 nM)
displacement of [H3]WIN 35428! 5-HTT (IC50 nM)
[H3]Citalopram! Selectivity
5-HTT/DAT|-| || R/S-90a ||H||>1000||>1000||-|-| || R/S-90b ||F||546||2580||4.7|-| || R/S-90c ||Cl||10||107||10.7|-| || R/S-90d ||Br||22||30||1.4|-| || R/S-90e ||I||7||12||1.7|-| || R/S-90f ||3,4-Cl2||3.35||6.52||1.9|-| || R-90g ||3,4-Cl2||3.27||4.67||1.4|-| || S-90h ||3,4-Cl2||47||58||1.2|-| || R/S-91a ||H||1990||11440||5.7|-| || R/S-91b ||F||>1000||>10000||-|-| || R/S-91c ||Cl||28.5||816||28.6|-| || R/S-91d ||Br||9||276||30.7|-| || R/S-91e ||I||42||72||1.7|-| || R/S-91f ||3,4-Cl2||3.08||64.5||20.9|-| || R-91g ||3,4-Cl2||2.34||31||13.2|-| || S-91h ||3,4-Cl2||56||2860||51.1|}

8-carba bridgehead replacements

8-carba 3-Aryl bicyclo[3.2.1]octanes! Structure! Compound #
(S. Singh)! DAT (IC50 nM)
displacement of [H3]WIN 35428! 5-HTT (IC50 nM)
[H3]Citalopram! Selectivity
5-HTT/DAT|-||| R/S-98a ||7.1 ± 1.7||5160 ± 580||726|-||| R/S-98b ||9.6 ± 1.8||33.4 ± 0.6||3.5|-||| R/S-98c ||14.3 ± 1.1||180 ± 65||12.6|}

N-alkyl

CompoundX2 Groupconfig8DATSERTNET
Cl 3′-phenylisoxazol-5′-yl β,β NCH2CH2CH2F - - -
Cl (3′-phenylisoxazol-5′-yl) β,β NCH2CH2F - - -
Altropane (IACFT) F CO2Me β,β NCH2CH=CHF - - -
FECNT[28] I CO2Me β,β NCH2CH2F- - -
I CO2Me β,β N-Prn 1.17- -
I CO2Me β,β NCH2CH=CH2 1.79- -
I CO2Me β,β NBun 0.76- -
I CO2Me β,β NCH2CH2CH2F 1.67- -
Ioflupane (FP-CIT) 123I CO2Me β,β NCH2CH2CH2F - - -
PE2IMeCO2Me β,β NCH2CH=CHI- - -
Cl CO2Me β,β NCH2CO2Et 1.93 10.1114
Cl CO2Me β,β NCH2CH2CO2Et 2.5635.2125
Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67227510

Bi- and tri-cyclic aza compounds and their uses.[29]

N-substituted 3β-phenylnortropanes
(including N-phthalimidoalkyl analogues of β-CIT)! Structure! Short Name
(S. Singh)! Nitrogen side-chain
(N8)! DAT
[<sup>3</sup>H]GBR 12935 Ki (nM)! 5-HTT
[<sup>3</sup>H]Paroxetine Ki (nM)! NET
[<sup>3</sup>H]Nisoxetine Ki (nM)! Selectivity
5-HTT/DAT! Selectivity
NET/DAT
Cocaine H350 ± 80>10000>30000>28.6-
GBR 12909 -0.06 ± 0.0252.8 ± 4.4>20000880-
WIN 35428
11b
H14.7 ± 2.9181 ± 21635 ± 11012.343.2
RTI-55
11e
H1.40 ± 0.200.46 ± 0.062.80 ± 0.400.32
82aCH2CH=CH222.6 ± 2.9ɑ----
82bCH2CH2CH343.0 ± 17.7ɑ----
82cCH2C6H558.9 ± 1.65b1073c-18.2-
82d(CH2)3C6H51.4 ± 0.2b133 ± 7c-95.0-
82e(CH2)5C6H53.4 ± 0.83b49.9 ± 10.2c-14.7-
83aCH2CH2CH2F1.20 ± 0.2948.7 ± 8.41000040.68333
83bCH2CH2F4.40 ± 0.3521.7 ± 8.3>100004.9-
84aCH2CH2CH2F3.50 ± 0.390.110 ± 0.0263.0 ± 4.00.0318
84bCH2CH2F4.00 ± 0.730.140 ± 0.0293.0 ± 17.00.0323.2
84cCH2CHF215.1 ± 3.79.6 ± 1.5>50000.6-
84dCH2CH2CH2Cl3.10 ± 0.570.32 ± 0.0696.0 ± 29.00.131.0
84eCH2CH2CH2Br2.56 ± 0.570.35 ± 0.08164 ± 470.164.1
84fCH2CH2CH2I38.9 ± 6.38.84 ± 0.5350000.2128
84gCH2...methylcyclopropane4.30 ± 0.871.30 ± 0.25198 ± 9.60.346.0
84hCH2CH2CH2OH5.39 ± 0.212.50 ± 0.20217 ± 190.540.2
84iCH2CH2(OCH3)26.80 ± 1.101.69 ± 0.09110 ± 7.70.216.2
84jCH2CO2CH311.9 ± 1.40.81 ± 0.1029.1 ± 1.00.072.4
84kCH2CON(CH3)212.2 ± 3.86.40 ± 1.70522 ± 1450.542.8
84lCH2CH2CH2OMs36.3 ± 2.117.3 ± 1.250000.5138
84mCOCH(CH3)22100 ± 140102 ± 23>100000.05-
84n(CH2)2Pht4.23 ± 0.480.84 ± 0.02441 ± 66.00.2104
84o(CH2)3Pht9.10 ± 1.100.59 ± 0.0774.0 ± 11.60.068.1
84p(CH2)4Pht2.38 ± 0.220.21 ± 0.02190 ± 18.00.0979.8
84q(CH2)5Pht2.40 ± 0.170.34 ± 0.0360.0 ± 3.100.125.0
84r(CH2)8Pht2.98 ± 0.300.20 ± 0.0275.0 ± 3.60.0725.2
84sdCH2CH=CH-CH315 ± 175 ± 5400 ± 805.026.7
84tdCH2C(Br)=CH230 ± 5200 ± 40>10006.7-
84udCH2CH=CH2I(E)30 ± 5960 ± 60295 ± 3332.09.8
84vdCH2C≡CH14 ± 1100 ± 30>10007.1-
84wdCH2C6H542 ± 12100 ± 17600 ± 1002.414.3
84xdCH2C6H4-2-CH393 ± 19225 ± 40>10002.4-
85adpara-H113 ± 41100 ± 20>10000.9-
85bdpara-Cl, meta-Cl29 ± 450 ± 6500 ± 1201.717.2
85cdpara-Me17 ± 7500 ± 30>100029.4-
85ddpara-CH(CH3)2500 ± 120450 ± 80>10000.9-
85edpara-n-C3H7500 ± 100300 ± 12750 ± 1600.61.5
  • ɑIC50 for displacement of [<sup>3</sup>H]cocaine. IC50 for cocaine = 67.8 ± 8.7 (nM)
  • bIC50 values for displacement of [<sup>3</sup>H]WIN 35428
  • cIC50 values for displacement of [<sup>3</sup>H]citalopram
  • dThe standard Ki value for the displacement of [<sup>3</sup>H]GBR 12935, [<sup>3</sup>H]paroxetine, and [<sup>3</sup>H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments
3β-(4-alkylthiophenyl)nortropanes! Structure ! Compound! R1! R2! Inhibition of [<sup>3</sup>H]WIN 35,428
@ DAT
IC50 (nM)! Inhibition of [<sup>3</sup>H]Paroxetine
@ 5-HTT
Ki (nM)! Inhibition of [<sup>3</sup>H]Nisoxetine
@ NET
Ki (nM)! NET/DAT
(uptake ratio)! NET/5-HTT
(uptake ratio)
See 7a—7h table
7a CH3CH3 9 ± 30.7 ± 0.2220 ± 1024314
7b C2H5CH3 232 ± 344.5 ± 0.51170 ± 3005260
8a CH3 H 28 ± 60.19 ± 0.0121 ± 60.8110
8b C2H5 H 177 ± 621.26 ± 0.05118 ± 130.794
9a CH3 FCH2CH2CH2112 ± 23 ± 1960 ± 1009320
9b C2H5 FCH2CH2CH21,200 ± 20027 ± 2>2,000274
10a CH3 CH2=CH2CH271 ± 255.5 ± 0.82,000 ± 50028364
10b C2H5 CH2=CH2CH21,100 ± 10047 ± 3>2,000243
11a CH3 CH3CH2CH274 ± 205.7 ± 0.61,200 ± 14016211
11b C2H5 CH3CH2CH2900 ± 30049 ± 6>2,000241

Bridged N-constrained phenyltropanes (fused/tethered)

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

p-methyl aryl front & back N-bridged phenyltropanes

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM)!Compound #
(S. Singh's #)!2β=R![<sup>3</sup>H]Mazindol binding![<sup>3</sup>H]DA uptake![<sup>3</sup>H]5-HT uptake![<sup>3</sup>H]NE uptake!selectivity
[<sup>3</sup>H]5-HT/[<sup>3</sup>H]DA
cocaineCO2CH3 375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4
(–)-40
(–)-128
54.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03
(+)-40
(+)-128
79 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01
(±)-40
(±)-128
61.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.04
29β62014208030
30β18649297.7
31β47.021128.5
29α4140201003920
30α396088506961150
45
129
6.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.07
42a
131a
n-Bu 4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.3
41a
130a
n-Bu 17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.8
42b
131b
Et 3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.3
50a
133a
n-Bu 149 ± 6149 ± 2810 ± 8051.7 ± 125.4
49a
132a
n-Bu 13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5
(–)-41050016500189070900
(+)-41850027600463038300
(–)-597409050119004650
(+)-5677010500251004530
RTI-4229/Coc-242N8/2β-C(O)CH(CO2Me)CH2N
para-chloro
7.67 ± 0.31ɑ226.54 ± 27.37b510.1 ± 51.4c
  • ɑValue for displacement of [<sup>3</sup>H]WIN 35,428 binding @ DAT
  • bValue for displacement of [<sup>3</sup>H]paroxetine binding to SERT
  • cValue for displacement of [<sup>3</sup>H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction.

3,4-Cl2 aryl front-bridged phenyltropanes

CodeCompoundDA (μM)NE (μM)5-HT (μM)
1(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0<sup>4,8</sup>]- undecan-11 -one O-methyl-oxime0.0120.00200.0033
2(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0<sup>4,8</sup>]- undecan-11-one0.180.0350.0075
3(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime0.01600.00090.0032
4(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol0.0750 0.0041 0.0028
5(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one0.120.0052 0.0026
6(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol0.250.00740.0018
7(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate0.21 0.00610.0075
8(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane 0.0220.00140.0001
  1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
  2. 2° amine is reacted with Br(CH2)nCO2Et.
  3. Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

  1. Remove N-Me
  2. Add ɣ-bromo-chloropropane
  3. Allow for cyclization with K2CO3 base and KI cat.

C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)


(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one

C3 to 1′ + 2′ (ortho) tropane locant dual arene bridged


Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.[30]

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

[3.3.1]azanonane analogues
displacement of bound [<sup>3</sup>H]WIN 35428! Structure! Compound #
(S. Singh)! Ki (nM)
Cocaine 32 ± 5
390 ± 220
WIN 35065-2 33 ± 17
310 ± 220
146a 4600 ± 510
146b 5730 ± 570
146c 3450 ± 310
146d 3470 ± 350
147 13900 ± 2010

Azabornane (outer ring contracted)

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.

Notes and References

  1. http://v3.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2008153870A1&KC=A1&FT=D&date=20080626&DB=EPODOC&locale=en_gb U.S. Patent Application Publication # US 2008/0153870 A1
  2. Jul 2013 . Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates. J Pharmacol Exp Ther . 346 . 1. 2–10 Fig. 1 . 10.1124/jpet.111.191056 . 3684841 . 23568856 . Schmitt. K. C.. Rothman. R. B.. Reith. M. E..
  3. Method of promoting smoking cessation.
  4. 12190324. 2002. Blough . B. E.. Keverline. Nie. Navarro. Kuhar. Carroll. Synthesis and transporter binding properties of 3β-4′-(phenylalkyl, -phenylalkenyl, and -phenylalkynyl)phenyltropane-2β-carboxylic acid methyl esters: evidence of a remote phenyl binding domain on the dopamine transporter. 45. 18. 4029–4037. Journal of Medicinal Chemistry. 10.1021/jm020098n . K. I. . Z. . H. . M. J. . F. I..
  5. 10.1021/jm020098n. 12190324. Synthesis and Transporter Binding Properties of 3β-[4'-(Phenylalkyl, -phenylalkenyl, and -phenylalkynl)phenyl]tropane-2β-carboxylic Acid Methyl Esters: Evidence of a Remote Phenyl Binding Domain on the Dopamine Transporter. Journal of Medicinal Chemistry. 45. 18. 4029–37. 2002. Blough. Bruce E.. Keverline. Kathryn I.. Nie. Zhe. Navarro. Hernán. Kuhar. Michael J.. Carroll. F. Ivy.
  6. Blough . etal . Sep 1996 . Synthesis and transporter binding properties of 3β-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 β-carboxylic acid methyl esters: serotonin transporter selective analogs . J Med Chem . 39 . 20. 4027–35 . 8831768 . 10.1021/jm960409s. 21616809 .
  7. 10.1016/j.bmcl.2003.07.014. 14592523. Synthesis and biological activity of 2-Carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes. Bioorganic & Medicinal Chemistry Letters. 13. 22. 4133–4137. 2003. Meltzer . P. C. . McPhee . M. . Madras . B. K. .
  8. 10.1021/jm00059a010. 8464040. Substituted 3-phenyltropane analogs of cocaine: Synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imaging. Journal of Medicinal Chemistry. 36. 7. 855–62. 1993. Meltzer. P. C.. Liang. A. Y.. Brownell. A. L.. Elmaleh. D. R.. Madras. B. K..
  9. Jin. Chunyang. Navarro. Hernán A.. Ivy Carroll. F.. Synthesis and structure–activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters. Bioorganic & Medicinal Chemistry. 17. 14. 2009. 5126–5132. 0968-0896. 10.1016/j.bmc.2009.05.052. 19523837. 2747657.
  10. R. H. Kline, Davies, E. Saikali, T. Sexton & S.R. Childers. Novel 2-substituted cocaine analogs: Binding properties at dopamine transport sites in rat striatum. European Journal of Pharmacology. 244. 1. 93–97. 1993. 8420793. 10.1016/0922-4106(93)90063-f.
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