Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors
Hm. Deutsch et al., Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors, J MED CHEM, 42(5), 1999, pp. 882-895
As part of a program to develop site-specific medications for cocaine abuse
, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane de
rivatives was synthesized and tested for inhibitory potency in [H-3]WIN 35,
428 binding and [H-3]dopamine uptake assays using rat striatal tissue. Sele
cted compounds were tested for their ability to substitute fur cocaine in r
at drug discrimination tests. Synthesis was accomplished by a series of Die
ls-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile
, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard ma
nipulations produced the aminomethyl side chain. Many of the compounds boun
d with high affinity (median IC50 = 223 nM) to the cocaine binding site as
marked by [H-3]WIN 35,428. Potency in the binding assay was strongly enhanc
ed by chlorine atoms in the 3- and/or 4-position on the aromatic ring and w
as little affected by corresponding methoxy groups. In the [2.2.2] series t
here was little difference in potency between cis and traits compounds or b
etween N,N-dimethylamines and primary amines. In the [2.2.1] series the tra
its exo compounds tended to be least potent against binding, whereas the ci
s exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold
more potent than 4-Cl trans-exo). Although the potencies of the bicyclic de
rivatives in the binding and uptake assays were highly correlated, some of
the compounds were 5-7-fold less potent at inhibiting [H-3]dopamine uptake
than [H-3]WIN 35,428 binding (for comparison, cocaine has a lower discrimin
ation ratio (DR) of 2.5). The DR values were higher for almost all primary
amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Mos
t of the compounds had Hill coefficients approaching unity, except for the
[2.2.2] 3,4-dichloro derivatives, which all had n(H) values of about 2.0. T
wo of the compounds were shown to fully substitute for cocaine in drug disc
rimination tests in rats, and one had a very long duration of action.