List of phenyltropanes

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Phenyltropanes are a family of chemical compounds originally derived from structural modification of cocaine. 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 & 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.) Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers. Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers).

3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.
File:Troparil structure.png
Troparil structure: c.f. U.S. Patent 5,496,953

2-Carboxymethyl esters

File:Epibati-tropane.svg
Epibati-tropane: U.S. Patent 6,479,509 containing a nitrogen heteroatom in the benzene ring formation.
WIN 35,065-2.svg
WIN 35428 structural formula.png
Chlorophenyltropane.png
RTI-32 structure.png
RTI-51.png
200px
200px
File:Tamagnan.png
Tamagnan:[1] pM activity for SERT
File:RTI-298.svg
RTI-298
(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>28,000 displacement value for NET ligand) that retains significant DAT & SERT affinity.

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.[lower-alpha 1] 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.[lower-alpha 2]

Certain phenyltropanes can be used as a smoking cessation aid. Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes
Short Name
(Singh's #)		 X (para-substitution) DA
[3H]WIN 35428		 5HT
[3H]paroxetine		 NE
[3H]nisoxetine		 selectivity
5-HTT/DAT		 selectivity
NET/DAT
cocaine H 102 ± 12
241 ± 18ɑ		 1045 ± 89
112 ± 2b		 3298 ± 293
160 ± 15c		 10.2
0.5d		 32.3
0.7e
WIN 35,065-2 (CPT)
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
WIN 35,428 (CFT)
11b		 F 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
11k NO2 10.1 ± 0.10 ? ? ? ?
RTI-29[4] NH2 9.8 5110 151 — —
RTI-31
11c		 Cl 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
RTI-32
11f		 Me 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
RTI-51 Br 1.69 10.6 37.4 — —
Iometopane (RTI-55)
11e		 I 1.26 ± 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
RTI-83
11g		 Et 55 ± 2.1 28.4 ± 3.8 4030 ± 381 0.5 73.3
RTI-11w
11w		 cis-propenyl 15 ± 1.2 7.1 ± 0.71 28,000 ± 300 0.5 1867
RTI-298[5] –≡–Ph 3.7 46.8 347 — —
RTI-436 –CH=CHPh 3.09 335 (31) 1960 (1181) — —
RTI-430 –C≡C(CH2)2Ph 6.28 2128 (198) 1470 (886) — —
Tamagnan[1] p-thiophene 12 0.017 189 — —
11d Br 1.81 ± 0.30 10.6 ± 0.24 37.4 ± 5.2 5.8 20.7
11h OH 12.1 ± 0.86 — — — —
11i OCH3 8.14 ± 1.3 — — — —
11j NH2 24.8 ± 1.3 — — — —
11l N3 2.12 ± 0.13 — — — —
11m CF3 13.1 ± 2.2 — — — —
11n NHCOCH3 64.2 ± 2.6 — — — —
11o NHCOC2H5 121 ± 2.7 — — — —
11p NHCO2C3H5 316 ± 48 — — — —
11q Sn(CH3)3 144 ± 37 — — — —
11r n-C3H7 68.5 ± 7.1 70.4 ± 4.1 3920 ± 130 1.0 57.2
11s CH(CH3)2 597 ± 52 191 ± 9.5 75000 ± 5820 0.3 126
11t CH-CH2 1.24 ± 0.2 9.5 ± 0.8 78 ± 4.1 7.7 62.9
11u C(=CH2)CH3 14.4 ± 0.3 3.13 ± 0.16 1330 ± 333 0.2 92.4
11v trans-CH=CHCH3 5.29 ± 0.53 11.4 ± 0.28 1590 ± 93 2.1 300
11x CH2CH=CH2 32.8 ± 3.1 28.4 ± 2.4 2480 ± 229 0.9 75.6
11y C≡CH 1.2 ± 0.1 4.4 ± 0.4 83.2 ± 2.8 3.7 69.3
11z C≡CCH3 2.37 ± 0.2 15.7 ± 1.5 820 ± 46 6.6 346
11aa Ph 10.3 ± 2.6f
29.4 ± 3.8ɑ		 — — — —
11bb 3β-2-naphthyl 3.32 ± 0.08f
3.53 ± 0.09ɑ		 — — — —
  • ɑKi value for displacement of [3H]DA uptake.
  • bKi value for displacement of [3H]5-HT uptake.
  • cKi value for displacement of [3H]NE uptake.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.
  • fIC50 for displacement of [3H]cocaine.
Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes[3]
Compound Short Name
(S. Singh)		 Y X DA 5HT NE Selectivity
5-HTT/DAT		 Selectivity
NET/DAT
250px
16a F H 23 ± 7.8 - - - -
16b Cl H 10.6 ± 1.8 - - - -
16c Br H 7.93 ± 0.08ɑ - - - -
16d I H 26.1 ± 1.7 - - - -
16e SnBu3 H 1100 ± 170 - - - -
17a CH3 F 2.95 ± 0.58 - - - -
17b CH3 Cl 0.81 ± 0.05 10.5 ± 0.05 36.2 ± 1.0 13.0 44.7
17c[6]
(Dichloropane)
(RTI-111)		 Cl Cl 0.79 ± 0.08 3.13 ± 0.36 18.0 ± 0.8 4.0 22.8
17d
(RTI-97)		 Br NH2 3.91 ± 0.59 181 282 - -
17e
(RTI-88)		 I NH2 1.35 ± 0.11 120 ± 4 1329 ± 124 88.9 984
17f I N3 4.93 ± 0.32 - - - -

ɑIC50 determined in Cynomolgous monkey caudate-putamen

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes[7]
Short Name
(All compounds tested as HCl salts)		 X
3′-(meta)		 Y
5′-(di-meta)		 OR
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 - - - 0.82 ± 0.05 0.95 ± 0.04 21.8 ± 0.6 27 23
7a 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

Para-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues[8]
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 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

(3,4-Disubstituted phenyl)-tropanes

200px
250px
Dichloropane.svg
RTI112.png
Compound
(+ S. Singh's name)		 X Y 2 Position config 8 DA 5-HT NE
RTI-318 β-naphthyl CO2Me β,β NMe 0.5 0.81 20
Dichloropane (RTI-111)[6]
17c		 Cl Cl CO2Me β,β NMe 0.79 3.13 18.0
RTI-88 [recheck]
17e		 NH2 I CO2Me β,β NMe 1.35 1329 320
RTI-97
17d		 NH2 Br CO2Me β,β NMe 3.91 181 282
RTI-112 Cl Me CO2Me β,β NMe 0.82 10.5 36.2
RTI-96 F Me CO2Me β,β NMe 2.95 76 520
RTI-295 Et I CO2Me β,β NMe 21.3 2.96 1349
RTI-353 (EINT) Et I CO2Me β,β NH 331 0.69 148
RTI-279 Me I CO2Me β,β NH 5.98 1.06 74.3
RTI-280 Me I CO2Me β,β NMe 3.12 6.81 484
Meltzer[9] catechol CO2Me β,β NMe >100 ? ?
Meltzer[9] OAc OAc CO2Me β,β NMe ? ? ?
Multi-substituted structures of 2β-ester-3β-phenyltropanes[3]
Compound Short Name
(S. Singh)		 R X IC50 (nM)
DAT
[3H]WIN 35428		 IC50 (nM)
5-HTT
[3H]paroxetine		 IC50 (nM)
NET
[3H]nisoxetine		 Selectivity
5-HTT/DAT		 Selectivity
NET/DAT
280px
23a CH(CH3)2 H 85.1 ± 2.5 23121 ± 3976 32047 ± 1491 272 376
23b C6H5 H 76.7 ± 3.6 106149 ± 7256 19262 ± 593 1384 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 ± 0.10 168 ± 1.8 235 ± 8.39 175 245
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 ± 3.9 1227 ± 176 967.6 ± 26.3 37.6 29.7
24e C6H4-3-CH3 Cl 9.37 ± 0.52 2153 ± 143 2744 ± 140 230 293
24f C6H4-4-CH3 Cl 27.4 ± 1.5 1203 ± 42 1277 ± 118 43.9 46.6
24g C6H4-2-CH3 Cl 3.91 ± 0.23 3772 ± 384 4783 ± 387 965 1223
24h C6H4-4-Cl Cl 55 ± 2.3 16914 ± 1056 4883 ± 288 307 88.8
24i C6H4-4-OCH3 Cl 71 ± 5.6 19689 ± 1843 1522 ± 94 277 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 ± 0.08 15.5 ± 0.72 102 ± 11 25.4 167
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 ± 1 4499 ± 557 3444 ± 44 235 180
26c cyclopropyl CH3 17.8 ± 0.76 485 ± 21 2628 ± 252 27.2 148
26d cyclobutyl CH3 3.74 ± 0.52 2019 ± 133 4738 ± 322 540 1267
26e cyclopentyl CH3 1.68 ± 0.14 1066 ± 109 644 ± 28 634 383
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 ± 0.90 5237 ± 453 2136 ± 208 639 261
26h C6H4-4-CH3 CH3 81.2 ± 16 15954 ± 614 4096 ± 121 196 50.4
26i C6H4-2-CH3 CH3 23.2 ± 0.97 11040 ± 504 25695 ± 1394 476 1107
26j C6H4-4-Cl CH3 117 ± 7.9 42761 ± 2399 9519 ± 864 365 81.3
26k C6H4-4-OCH3 CH3 95.6 ± 8.8 82316 ± 7852 3151 ± 282 861 33.0
  • ɑKi value for displacement of [3H]DA uptake.
  • bKi value for displacement of [3H]5-HT uptake.
  • cKi value for displacement of [3H]NE uptake.
  • d[3H]5-HT uptake to [3H]DA uptake ratio.
  • e[3H]NE uptake to [3H]DA uptake ratio.
File:Exo-2-Phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic Acid.jpg
exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid

With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands)[10] cf. EXP-561 & BTQ.
2β-Carboxamide-3β-Phenyltropanes[3]
Compound Short Name
(S. Singh)		 R X IC50 (nM)
DAT
[3H]WIN 35428		 IC50 (nM)
5-HTT
[3H]Paroxetine		 IC50 (nM)
NET
[3H]Nisoxetine		 Selectivity
5-HTT/DAT		 Selectivity
NET/DAT
29a NH2 CH3 41.8 ± 2.45 6371 ± 374 4398 ± 271 152 105
29b N(CH2CH3)2 CH3 24.7 ± 1.93 33928 ± 2192 6222 ± 729 1374 252
29c N(OCH3)CH3 CH3 2.55 ± 0.43 3402 ± 353 422 ± 26 1334 165
29d 4-morpholine CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547 2017

Carboxyaryl

200px
RTIoneonethree.png
RTI-120 structure.png
Compound X 2 Position config 8 DA 5-HT NE
RTI-122 I -CO2Ph β,β NMe 1.50 184 3,791
RTI-113 Cl -CO2Ph β,β NMe 1.98 2,336 2,955
RTI-277 NO2 -CO2Ph β,β NMe 5.94 2,910 5,695
RTI-120 [recheck] Me -CO2Ph β,β NMe 3.26 24,471 5,833
RTI-116 Cl -CO2(p-C6H4I) β,β NMe 33 1,227 968
RTI-203 Cl CO2(m-C6H4Me) β,β NMe 9.37 2153 2744
RTI-204 Cl -CO2(o-C6H4Me) β,β NMe 3.91 3,772 4,783
RTI-205 Me -CO2(m-C6H4Me) β,β NMe 8.19 5,237 2,137
RTI-206 Cl -CO2(p-C6H4Me) β,β NMe 27.4 1,203 1,278

Carboxyalkyl

300px
RTI-121.png
RTI-150.png
Code X 2 Position config 8 DA 5-HT NE
RTI-77 Cl CH2C2(3-iodo-p-anilino) β,β NMe 2.51 — 2247
RTI-121 I -CO2Pri β,β NMe 0.43 66.8 285
RTI-153 I -CO2Pri β,β NH 1.06 3.59 132
RTI-191 I -CO2Prcyc β,β NMe 0.61 15.5 102
RTI-114 Cl -CO2Pri β,β NMe 1.40 1,404 778
RTI-278 NO2 -CO2Pri β,β NMe 8.14 2,147 4,095
RTI-190 Cl -CO2Prcyc β,β NMe 0.96 168 235
RTI-193 Me -CO2Prcyc β,β NMe 1.68 1,066 644
RTI-117 Me -CO2Pri β,β NMe 6.45 6,090 1,926
RTI-150 Me -CO2Bucyc β,β NMe 3.74 2,020 4,738
RTI-127 Me -CO2C(H)Et2 β,β NMe 19 4500 3444
RTI-338 ethyl -CO2C2Ph β,β NMe 1104 7.41 3366

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.

Amides

U.S. Patent 5,736,123

200px
RTI-229 structure.png
200px
Code X 2 Position config 8 DA NE 5-HT
RTI-106 Cl CON(H)Me β,β NMe 12.4 1511 1312
RTI-118 Cl CONH2 β,β NMe 11.5 4267 1621
RTI-222 Me morpholinyl β,β NMe 11.7 — >100K
RTI-129 Cl CONMe2 β,β NMe 1.38 942 1079
RTI-146 Cl CONHCH2OH β,β NMe 2.05 144 98
RTI-147 Cl CON(CH2)4 β,β NMe 1.38 3,949 12,394
RTI-156 Cl CON(CH2)5 β,β NMe 6.61 5832 3468
RTI-170 Cl CON(H)CH2C≡CH β,β NMe 16.5 1839 4827
RTI-172 Cl CON(H)NH2 β,β NMe 44.1 3914 3815
RTI-174 Cl CONHCOMe β,β NMe 158 >43K >125K
RTI-182 Cl CONHCH2COPh β,β NMe 7.79 1722 827
RTI-183✲ Cl CON(OMe)Me β,β NMe 0.85 549 724
RTI-186 Me CON(OMe)Me β,β NMe 2.55 442 (266) 3400 (309)
RTI-198 Cl CON(CH2)3 β,β NMe 6.57 990 813
RTI-196 Cl CONHOMe β,β NMe 10.7 9907 >43K
RTI-201 Cl CONHNHCOPh β,β NMe 91.8 >20K >48K
RTI-208 Cl CONO(CH2)3 β,β NMe 1.47 998 2470
RTI-214 Cl CON(-CH2CH2-)2O β,β NMe 2.90 8545 >88K
RTI-215 Cl CONEt2 β,β NMe 5.48 ? 9432
RTI-217 Cl CONH(m-C6H4OH) β,β NMe 4.78 >30K >16K
RTI-218✲ Cl CON(Me)OMe β,β NMe 1.19 520 1911
RTI-226 Cl CONMePh β,β NMe 45.0 ? 24K
RTI-227 I CONO(CH2)3 β,β NMe 0.75 446 230
RTI-229[11] I CON(CH2)4 β,β NMe 0.37 991 1,728

✲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.

Acyl

WF-23.svg
WF-31.svg
WF-11.svg
WF-33.svg
#
(#)		 X Y 2 Position config 8 DA 5-HT NE
WF-23
(39n)		 β-naphthyl C(O)Et β,β NMe 0.115 0.394 No data
WF-31 -Pri H C.O.Et β,β NMe 615 54.5 No data
WF-11
(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
WF-33 6-MeoBN C(O)Et α,β NMe 0.13 2.24 No data
2β-acyl-3β-phenyltropane structures[lower-alpha 3]
S. Singh's
alphanumeric
assignation
(name)		 R1 R2 DAT

[125I]RTI-55 IC50 (nM)

 5-HTT

[3H]Paroxetine Ki (nM)

 Selectivity

5-HTT/DAT
cocaine 173 ± 19 — —
Troparil
11a
(WIN 35065-2)		 98.8 ± 12.2 — —
WF-25
39a		 C2H5 C6H5 48.3 ± 2.8 1005 ± 112 20.8
39b CH3 C6H5 114 ± 22 1364 ± 616 12.0
39c C2H5 C6H4-4-F 15.3 ± 2.8 630 ± 67 41.2
39d CH3 C6H4-4-F 70.8 ± 13 857 ± 187 12.1
WF-11
39e		 C2H5 C6H4-4-CH3 8.2 ± 1.6 131 ± 1 16.0
(+)-39e C2H5 C6H4-4-CH3 4.21 ± 0.05 74 ± 12 17.6
(-)-39e C2H5 C6H4-4-CH3 1337 ± 122 >10000 —
39f CH3 C6H4-4-CH3 9.8 ± 0.5 122 ± 22 12.4
39g CH3 C6H4-4-C2H5 152 ± 24 78.2 ± 22 0.5
39h C2H5 C6H4-4-CH(CH3)2 436 ± 41 35.8 ± 4.4 0.08
39i C2H5 C6H4-4-C(CH3)3 2120 ± 630 1771 ± 474 0.8
39j C2H5 C6H4-4-C6H5 2.29 ± 1.08 4.31 ± 0.01 1.9
39k C2H5 C6H4-2-CH3 1287 ± 322 710000 >7.8
39l C2H5 1-naphthyl 5.43 ± 1.27 20.9 ± 2.9 3.8
39m CH3 1-naphthyl 10.1 ± 2.2 25.6 ± 5.1 2.5
WF-23
39n		 C2H5 2-naphthyl 0.115 ± 0.021 0.394 ± 0.074 3.5
39o CH3 2-naphthyl 0.28 ± 0.11 1.06 ± 0.36 3.8
39p C2H5 C6H4-4-CH(C2H5)2 270 ± 38 540 ± 51 2.0
39q C2H5 C6H4-4-C6H11 320 ± 55 97 ± 12 0.30
39r C2H5 C6H4-4-CH=CH2 0.90 ± 0.34 3.2 ± 1.3 3.5
39s C2H5 C6H4-4-C(=CH2)CH3 7.2 ± 2.1 0.82 ± 0.38 0.1

Ester reduction

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

200px
Code X 2 Position config 8 DA 5-HT NE
RTI-100 F -CH2OH β,β NMe 47 4741 no data
RTI-101 I -CH2OH β,β NMe 2.2 26 no data
RTI-99 Br -CH2OH β,β NMe 1.49 51 no data
RTI-93 Cl -CH2OH β,β NMe 1.53 204 43.8
RTI-105 Cl -CH2OAc β,β NMe 1.60 143 127
RTI-123 Cl -CH2OBz β,β NMe 1.78 3.53 393
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2.93 1.48

β,α Stereochemistry

300px
300px
Compound (RTI #)
(S. Singh's #)		 X 2 Group config 8 DA IC50 (nM)
[3H]WIN 35428		 5-HT IC50 (nM)
[3H]paroxetine		 NE IC50 (nM)
[3H]nisoxetine		 selectivity
5-HTT/DAT		 selectivity
NET/DAT
RTI-140
20a		 H CO2Me β,α NMe 101 ± 16 5,701 ± 721 2,076 ± 285 56.4 20.6
RTI-352 U.S. Patent 6,358,492
20d		 I CO2Me β,α NMe 2.86 ± 0.16 64.9 ± 1.97 52.4 ± 4.9 22.8 18.4
RTI-549 Br CO2Me β,α NMe — — — — —
RTI-319 U.S. Patent 7,011,813 BN CO2Me β,α NMe 1.1 11.4 70.2 — —
RTI-286 U.S. Patent 7,011,813
20b		 F CO2Me β,α NMe 21 ± 0.57 5062 ± 485 1231 ± 91 241 58.6
RTI-274 U.S. Patent 7,291,737 F CH2O(3′,4′-MD-phenyl) β,α NH 3.96 5.62 14.4 — —
RTI-287 Et CO2Me β,α NMe 327 1687 17,819 — —
20c 2.4 ± 0.2 998 ± 120 60.1 ± 2.4 416 25.0
20e 10.2 ± 0.08 4250 ± 422 275 ± 24 417 27.0

800px

α,β Stereochemistry

CA 2112084 

Brasofensine.svg
Compound DA (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]octane 0.39 <1 50 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane 0.1 1 25 0 0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane 0.016 0.25 50 + +++
Tesofensine chemical structure.png
NStwothreefivenine.png

U.S. Patent 2,001,047,028

Compound X 2 Group config 8 DA 5-HT NE
Brasofensine Cl2 methyl aldoxime α,β NMe — — —
Tesofensine Cl2 ethoxymethyl α,β NMe 65 11 1.7
NS-2359 (GSK-372,475) Cl2 Methoxymethyl α,β NH — — —

A1 WO 2004072075 A1 

Test Compound DA 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 salt 0.062 0.035 0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.062 0.15 0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.10 0.048 0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt 0.088 0.051 0.013

Aryl-Tropenes

WO2004113297 

Test compound DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene 0.26 0.028 0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene 0.058 0.013 0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene 0.034 0.018 0.00023
WO 9713770 
8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 0.079 0.026 0.0047

U.S. Patent 2,001,047,028

Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 18 4.9 0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 1.5 0.5 0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 22.00 8.00 0.0036
File:LBT-999.svg
LBT-999, a radio-ligand.

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[12] to the energetically more favorable trans configuration. This can happen to cocaine also.

3-Substituted-isoxazol-5-yl

File:3-R-isoxazol-5-yl.svg

N-methylphenyltropanes with 1R β,β stereochemistry.
Code X R DA NE 5HT
RTI-165 Cl 3-methylisoxazol-5-yl 0.59 181 572
RTI-171 Me 3-methylisoxazol-5-yl 0.93 254 3818
RTI-180 I 3-methylisoxazol-5-yl 0.73 67.9 36.4
RTI-177 Cl 3-phenylisoxazol-5-yl 1.28 504 2418
RTI-176 Me 3-phenylisoxazol-5-yl 1.58 398 5110
RTI-181 I 3-phenylisoxazol-5-yl 2.57 868 100
RTI-184 H methyl 43.3 — 6208
RTI-185 H Ph 285 — >12K
RTI-334 Cl 3-ethylisoxazol-5-yl 0.50 120 3086
RTI-335 Cl isopropyl 1.19 954 2318
RTI-336 Cl 3-(4-methylphenyl)isoxazol-5-yl 4.09 1714 5741
RTI-337 Cl 3-t-butyl-isoxazol-5-yl 7.31 6321 37K
RTI-345 Cl p-chlorophenyl 6.42 5290 >76K
RTI-346 Cl p-anisyl 1.57 762 5880
RTI-347 Cl p-fluorophenyl 1.86 918 7257
RTI-354 Me 3-ethylisoxazol-5-yl 1.62 299 6400
RTI-366 Me R = isopropyl 4.5 2523 (1550) 42,900 (3900)
RTI-371 Me p-chlorophenyl 8.74 >100K (60,200) >100K (9090)
RTI-386 Me p-anisyl 3.93 756 (450) 4027 (380)
RTI-387 Me p-fluorophenyl 6.45 917 (546) >100K (9400)

3-Substituted-1,2,4-oxadiazole

File:RTI-155.jpg
RTI-155
200px
RTI-126.png
Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Code
(Singh's #)		 X R DA NE 5HT 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[13]
(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 Cl 3-(p-chlorophenyl)-1,2,4-oxadiazole 4.1 4069 404
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
File:RTI-470 structure.png
RTI-470 structure:[14]
220px
RTI-371 structure.png
N-methylphenyltropanes with 1R β,β stereochemistry.
Code X 2 Group DA NE 5HT
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 Cl 5-phenyl-oxazol-2-yl 19.7 496 1116
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
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[15] 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)
File:Heterocyclic phenyltropane syntheses p2.png
Above is taken from: RTI, Kuhar, et al. U.S. Patent 5,935,953 (1999).

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

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.[3]

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 hundred fold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake.

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 cyclopenta dienyl (Cp) ligand.[3]

Displacement of Receptor-Bound [3H]WIN 35428 and Inhibition of [3H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes[3]
Structure Compound #
(S. Singh)
Systematic name		 Ki (nM)ɑ IC50 (nM) selectivity
binding/uptake
Cocaine 32 ± 5
388 ±221		 405 12.6
11a 33 ± 17
314 ± 222		 373 11.3
150px
 21a
[η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium		 17 ± 15b
224 ± 83		 418 24.6
210px
 21b
[η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate		 2280 ± 183 3890 1.7
  • 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

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		 89.4 53.7 186 0.6
11c 0.83 ± 00.7 28.5 ± 0.9 34.3
11f 5.76 6.92 23.2 1.2
160px
 41a (CH2)2CH3 H 12.2 6.89 86.8 0.6
190px
 41b (CH2)3C6H5 H 16 ± 2a 43 ± 13b 2.7
160px
 42 (CH2)2CH3 F 5.28 1.99 21.7 0.4
160px
 43a CH=CH2 Cl 0.59 ± 0.15 2.47 ± 0.5 4.2
160px
 43b E-CH=CHCl Cl 0.42 ± 0.04 1.13 ± 0.27 2.7
160px
 43c Z-CH=CHCl Cl 0.22 ± 0.02 0.88 ± 0.05 4.0
160px
 43d E-CH=CHC6H5 Cl 0.31 ± 0.04 0.66 ± 0.01 2.1
160px
 43e Z-CH=CHC6H5 Cl 0.14 ± 0.07 0.31 ± 0.09 2.2
160px
 43f CH2CH3 Cl 2.17 ± 0.20 2.35 ± 0.52 1.1
160px
 43g (CH2)2CH3 Cl 0.94 ± 0.08 1.08 ± 0.05 1.1
160px
 43h (CH2)3CH3 Cl 1.21 ± 0.18 0.84 ± 0.05 0.7
160px
 43i (CH2)5CH3 Cl 156 ± 15 271 ± 3 1.7
160px
 43j (CH2)2C6H5 Cl 1.43 ± 0.03 1.54 ± 0.08 1.0
160px
 44a (CH2)2CH3 CH3 1.57 1.10 10.3 0.7
160px
 44b (CH2)3CH3 CH3 1.82 1.31 15.1 0.7
110px
 45 (CH2)2CH3 H 74.9 30.2 389 0.4
110px
 46 (CH2)2CH3 F 21.1 12.1 99.6 0.6
110px
 47a (CH2)2CH3 CH3 8.91 11.8 50.1 1.3
120px
 47b (CH2)3CH3 CH3 11.4 10.1 51.0 0.9

aKi value for displacement of WIN 35428.
bIC50 value.

N-alkyl

200px
Altropane.svg
Ioflupane.png
Compound X 2 Group config 8 DAT SERT NET
FP-β-CPPIT Cl 3′-phenylisoxazol-5′-yl β,β NCH2CH2CH2F - - -
FE-β-CPPIT Cl (3′-phenylisoxazol-5′-yl) β,β NCH2CH2F - - -
Altropane F CO2Me β,β NCH2CH=CHF - - -
RTI-310 U.S. Patent 5,736,123 I CO2Me β,β N-Prn 1.17 - -
RTI-311 I CO2Me β,β NCH2CH=CH2 1.79 - -
RTI-312 U.S. Patent 5,736,123 I CO2Me β,β NBun 0.76 - -
RTI-313 U.S. Patent 5,736,123 I CO2Me β,β NCH2CH2CH2F 1.67 - -
Ioflupane ¹²³I CO2Me β,β NCH2CH2CH2F - - -
RTI-251 Cl CO2Me β,β NCH2CO2Et 1.93 10.1 114
RTI-252 Cl CO2Me β,β NCH2CH2CO2Et 2.56 35.2 125
RTI-242 Cl β,β (bridged) -C(O)CH(CO2Me)CH2N 7.67 227 510

Bi- and tri-cyclic aza compounds and their uses U.S. Patent 6,150,376 WO 0007994 

Tricyclic/N-constrained (inclu. N-bridged/fused/tethered)

Constrained tropane:[16][17]
Tricyclic tropanes[18]
Compound X Y R SERT Ki (nM) DAT Ki (nM) NET Ki (nM)
1 Cl Cl CH2OCOMe 1.6 1870 638
2 Br Cl CO2Me 2.3 5420 459
3 I Cl CH2OCOPh 0.06 >10K >10K

U.S. Patent 6,150,376

File:Koz US6150376.png
Structures mentioned in US6150376 table of Ki data.
File:Alt2D-bridged-phenyltropane-no42a.jpg
Alternate 2D rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the contrained nitrogen. Compare JNJ-7925476, tametraline and similar compounds.
Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes Ki (nM)
Compound #
(S. Singh's #)		 2β=R [3H]Mazindol binding [3H]DA uptake [3H]5-HT uptake [3H]NE uptake selectivity
[3H]5-HT/[3H]DA
cocaine CO2CH3 375 ± 68 423 ± 147 155 ± 40 83.3 ± 1.5 0.4
(–)-40
(–)-128		 54.3 ± 10.2 60.3 ± 0.4 1.76 ± 0.23 5.24 ± 0.07 0.03
(+)-40
(+)-128		 79 ± 19 114 ± 28 1.48 ± 0.07 4.62 ± 0.31 0.01
(±)-40
(±)-128		 61.7 ± 8.5 60.3 ± 0.4 2.32 ± 0.23 2.69 ± 0.12 0.04
29β 620 1420 8030 — —
30β 186 492 97.7 — —
31β 47.0 211 28.5 — —
29α 4140 20100 3920 — —
30α 3960 8850 696 1150 —
45
129		 6.86 ± 0.43 24.0 ± 1.3 1.77 ± 0.04 1.06 ± 0.03 0.07
42a
131a		 n-Bu 4.00 ± 0.07 2.23 ± 0.12 14.0 ± 0.6 2.99 ± 0.17 6.3
41a
130a		 n-Bu 17.2 ± 1.13 10.2 ± 1.4 78.9 ± 0.9 15.0 ± 0.4 7.8
42b
131b		 Et 3.61 ± 0.43 11.3 ± 1.1 25.7 ± 4.3 4.43 ± 0.01 2.3
50a
133a		 n-Bu 149 ± 6 149 ± 2 810 ± 80 51.7 ± 12 5.4
49a
132a		 n-Bu 13.7 ± 0.8 14.2 ± 0.1 618 ± 87 3.84 ± 0.35 43.5
(–)-4 10500 16500 1890 70900 —
(+)-4 18500 27600 4630 38300 —
(–)-5 9740 9050 11900 4650 —
(+)-5 6770 10500 25100 4530 —

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] U.S. Patent 5,998,405

File:Fused Tropane.png
Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. U.S. Patent 5,998,405
Code Compound DA (μM) NE (μM) 5-HT (μM)
1 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime 0.012 0.0020 0.0033
2 (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one 0.18 0.035 0.0075
3 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime 0.0160 0.0009 0.0032
4 (1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol 0.0750 0.0041 0.0028
5 (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one 0.12 0.0052 0.0026
6 (1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol 0.25 0.0074 0.0018
7 (1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate 0.21 0.0061 0.0075
8 (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane 0.022 0.0014 0.0001
  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.

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

File:Cocaine analogs - thiophenes and furans.svg
U.S. Patent 7,247,643
Code Compound DA (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 salt 0.30 0.0019 0.00052
2 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.36 0.0036 0.00042
3 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.31 0.00090 0.00036
4 (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt 0.92 0.0030 0.00053
5 (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.074 0.0018 0.00074
6 (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt 0.19 0.0016 0.00054

N-replaced (S,O,C)

Tropoxane.png
Thia.png
Compound X 2 Group config 8 DA 5-HT NE
Tropoxane Cl,Cl CO2Me (racemic) β,β O 3.3 6.5 No data
Meltzer.png

Diaryl

File:Hanna et al.png
Hanna et al. (2007)[19]
File:ZIENT.png
ZIENT:[20]

Radiolabeled

File:Radiolabel Tropane.png
Radiolabel Tropane:[21] Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.
Code SERT Ki (nM) NET Ki (nM) DAT Ki (nM) Radiolabel In vivo study Refs.
1 0.2 102.2 29.9 11C Non-human primate [22]
2 0.2 31.7 32.6 11C Non-human primate [23]
3 0.05 24 3.47 123I Rat [24]
4 0.08 28 13 18F Non-human primate [25]
5 0.11 450 22 11C Rat, monkey [26]
File:N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane.png
IPT (N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with 123I or 125I and used as a ligand to map several MATs

Transition metal complexes

"Transition metal" N-chelated phenyltropanes[3]
Structure Compound #
(S. Singh)		 X = para- / 4′-
Substitution		 Configuration DAT (IC50 nM)
displacement of [H3]WIN 35428		 5-HTT (IC50 nM)
[H3]Citalopram		 Selectivity
5-HTT/DAT
WIN 35428 F - 11.0 ± 1.0 160 ± 20 14.5
73
TRODAT-1d		 Cl - R=13.9, S=8.42b - -
74
TROTEC-1		 F - high affinity site = 0.15 ± 0.04c
low affinity site = 20.3 ± 16.1c		 - -
200px
 89a F 2β 5.99 ± 0.81 124 ± 17 20.7
200px
 89b F 2α 2960 ± 157 5020 ± 1880 1.7
200px
 89c 3,4-Cl2 2β 37.2 ± 3.4 264 ± 16 7.1
200px
 89d Cl - 0.31 ± 0.03ɑ - -
  • ɑKi value for displacement of [125I]IPT radioligand.
  • bR- & S- isomer values are Ki (nM) for displacement of [125I]IPT with technetium-99m replaced by rhenium
  • cIC50 (nM) values for displacement of [3H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC50 for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
  • d[2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1R-(exo, exo)]-[99mTc]technetium

Irreversible

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Irreversible (phenylisothiocyanate) binding ligand (Lua error in package.lua at line 80: module 'strict' not found.)[27] RTI-76:[28] 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.

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

Nortropanes (N-demethylated)

NStwothreefivenine.png

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.[29] 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.[30]

Selected ββ Nortropanes
Code X DA 5HT NE
RTI-142 F 4.39 68.6 18.8
RTI-98 I 0.69 0.36 11.0
RTI-110 Cl 0.62 4.13 5.45
RTI-173 Et 49.9 8.13 122
N-demethylating various β,β p-HC-phenyltropanes
X [3H]Paroxetine [3H]WIN 35,428 [3H]Nisoxetine
Ethyl 28.4 → 8.13 55 → 49.9 4,029 → 122
vinyl 9.5 → 2.25 1.24 → 1.73 78 → 14.9
Ethynyl 4.4 → 1.59 1.2 → 1.24 83.2 → 21.8
1-Propyl 70.4 → 26 68.5 → 212 3,920 → 532
trans-propenyl 11.4 → 1.3 5.29 → 28.6 1,590 → 54
cis-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147
Allyl 28.4 → 6.2 32.8 → 56.5 2,480 → 89.7
1-Propynyl 15.7 → 3.16 2.37 → 6.11 820 → 116
i-Propyl 191 → 15.1 597 → 310 75,000 → ?
2-Propenyl 3.13 → 0.6 14.4 → 23 1,330? → 144
N-Demethylating phenyltropanes to find a NRI
Isomer 4′ 3′ NE DA 5HT
β,β Me H 60 → 7.2 1.7 → 0.84 240 → 135
β,β F H 835 → 18.8 15.7 → 4.4 760 → 68.6
β,β Cl H 37 → 5.45 1.12 → 0.62 45 → 4.13
β,α Me H 270 → 9 10.2 → 33.6 4250 → 500
β,α F H 1200 → 9.8 21 → 32.6 5060 → 92.4
β,α Cl H 60 → 5.41 2.4 → 3.1 998 → 53.3
β,α F Me 148 → 4.23 13.7 → 9.38 1161 → 69.8
β,α Me F 44.7 → 0.86 7.38 → 9 1150 → 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).[31]

Thiophenyltropanes

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Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. Patent 6,329,520, U.S. Patent 7,011,813, U.S. Patent 6,531,483, and U.S. Patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Cycloalkane-ring alterations of the tropane ring system

Azanonane

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

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

Azabornane

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

[2.2.1]azabornane analogues displacement of bound [3H]WIN 35428[3]
Structure Compound #
(S. Singh)		 Ki (nM)
Cocaine 32 ± 5
390 ± 220
WIN 3506-2 33 ± 17
310 ± 220
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 155a 60,400 ± 4,800
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 155b 96,500 ± 42
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 155c 5,620 ± 390
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 155d 18,900 ± 1,700

Piperidine analogues

Phenyltropane piperidine analogues[3]
Structure Compound #
(S. Singh)		 X = para- / 4′-
Substitution		 R = 2-tropane position DAT (IC50 nM)
[H3]WIN 35428 binding displacement		 DA (IC50 nM)
[H3]DA uptake		 Selectivity
Uptake/Binding
Cocaine H CO2Me 102 ± 9 239 ± 1 2.3
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(±)-166a Cl β-CO2CH3 53.7 ± 1.9 37.8 ± 7.9 0.7
(-)-166a Cl β-CO2CH3 24.8 ± 1.6 85.2 ± 2.6 3.4
(+)-166a Cl β-CO2CH3 1360 ± 125 5090 ± 172 3.7
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(-)-167a Cl β-CO2OH 75.3 ± 6.2 49.0 ± 3.0 0.6
(+)-167a Cl β-CO2OH 442 ± 32 — —
150px
(-)-168a Cl β-CO2OAc 44.7 ± 10.5 62.9 ± 2.7 1.4
(+)-168a Cl β-CO2OAc 928 ± 43 2023 ± 82 2.2
150px
(-)-169a Cl β-n-Pr 3.0 ± 0.5 8.3 ± 0.6 2.8
150px
(-)-170a H β-CO2CH3 769 ± 19 — —
150px
(±)-166b Cl α-CO2CH3 197 ± 8 — —
(+)-166b Cl α-CO2CH3 57.3 ± 8.1 34.6 ± 3.2 0.6
(-)-166b Cl α-CO2CH3 653 ± 38 195 ± 8 0.3
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(+)-167b Cl α-CO2OH 240 ± 18 683 ± 47 2.8
150px
(+)-168b Cl α-CO2OAc 461 ± 11 — —
150px
(+)-169b Cl α-n-Pr 17.2 ± 0.5 23.2 ± 2.2 1.3

Misc.

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200px
Code X 2 Position config 8 DA 5-HT NE
RTI-102 I CO2H β,β NMe 474 1928 43,400
RTI-103 Br CO2H β,β NMe 278 3070 17,400
RTI-104 F CO2H β,β NMe 2744 >100K >100K
RTI-108 Cl -CH2Cl β,β NMe 2.64 98 129.8
RTI-241 Me -CH2CO2Me β,β NMe 1.02 619 124
RTI-139 Cl -CH3 β,β NMe 1.67 85 57
RTI-161 Cl -C≡N β,β NMe 13.1 1887 2516
RTI-230 Cl H3C–C=CH2 β,β NMe 1.28 57 141
RTI-240 Cl -CHMe2 β,β NMe 1.38 38.4 84.5
RTI-145 Cl -CH2OCO2Me β,β NMe 9.60 2,932 1,478
RTI-158 Me -C≡N β,β NMe 57 5095 1624
RTI-131 Me -CH2NH2 β,β NMe 10.5 855 120
RTI-164 Me -CH2NHMe β,β NMe 13.6 2246 280
RTI-132 Me -CH2NMe2 β,β NMe 3.48 206 137
RTI-239 Me -CHMe2 β,β NMe 0.61 114 35.6
RTI-338 Et -CO2CH2Ph β,β NMe 1104 7.41 3366
RTI-348 H -Ph β,β NMe 28.2 >34,000 2670

Phenyltropane based Benztropines

Benztropine phenyltropane:[32]

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

One patent claims a series of compounds with biotin-related sidechains are pesticides.[13]

Code X[clarification needed] 2 Position[clarification needed] config DA NE 5-HT
RTI-224 Me F1c β,β 4.49 — 155.6
RTI-233 Me F2 β,β 4.38 516 73.6
RTI-235 Me F3 d β,β 1.75 402 72.4
RTI-236 Me B1 d β,β 1.63 86.8 138
RTI-237 Me B2 d β,β 7.27 258 363
RTI-244 Me B3 d β,β 15.6 1809 33.7
RTI-245 Cl F4 c β,β 77.3 — —
RTI-246 Me F4 c β,β 50.3 3000 —
RTI-248 Cl F6 c β,β 9.73 4674 6.96
RTI-249 Cl F1 c β,β 8.32 5023 81.6
RTI-266 Me F2 β,β 4.80 836 842
RTI-267 Me F7 wrong β,β 2.52 324 455
RTI-268 Me F7 right β,β 3.89 1014 382
RTI-269 Me F8 β,β 5.55 788 986

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See also

References

  1. ↑ [3] ←Page #970 (46th page of article) §B, 10th line
  2. ↑ [3] ←Page #971 (47th page of article) 1st ¶, 10th line
  3. ↑ [3] ←Page #941 (17th page of article) Figure 10
  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ J Pharmacol Exp Ther. 2013 Jul; 346(1): 2–10. Fig. 1. Published online 2013 Jul. doi: 10.1124/jpet.111.191056
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000, ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Mirror hotlink.
  4. ↑ U.S. Patent 6,479,509 Method of promoting smoking cessation.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Monoamine Transporter Binding Properties of 3β-(Substituted phenyl)tropane-2β-carboxylic Acid Methyl Esters
  8. ↑ 3β-(4-Methoxyphenyl)tropane-2β-carboxylic Acid Ester Analogs
  9. ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ exo-2-Phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic Acid: A New Constrained Proline Analogue. Source: Tetrahedron Letters, Volume 36, Number 39, 25 September 1995, pp. 7123-7126(4)
  11. ↑ http://www3.interscience.wiley.com/journal/55001898/abstract
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 Methods for controlling invertebrate pests using cocaine receptor binding ligands. U.S. Patent 5,935,953
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ PMC 2671940
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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