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

Abstract

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 derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis 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 derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination 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]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.

Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593

“…If so, U69593 should have also attenuated the effects of WIN 35,428 which binds with high affinity to the transporter Deutsch et al 1999) and displaces cocaine in in vitro studies Stathis et al 1995). However, in the present experiment a dose of U69593 that attenuated cocaine-produced cocaine seeking failed to reduce the ability of WIN 35,428 to reinstate extinguished cocaine-taking behavior.…”

Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development

“…When combined with cocaine, however, 4-Cl-BZT enhanced rather than blocked cocaine-induced DA accumulation in the nucleus accumbens and the discriminative stimulus effects of cocaine in rats (Tolliver et al 1999;Katz et al 2001). Although other DA-sparing cocaine antagonists have been proposed (Bennett et al 1995;Deutsch et al 1999), none have undergone extensive testing. There remains, then, a need for "proof of principle" testing and for development of drugs with higher binding:inhibition ratios.…”

Biochemical and Behavioral Characterization of Novel Methylphenidate Analogs

“…The DR is an empirical measure utilized in our laboratory as a preliminary screen to identify potential cocaine antagonists. Because it represents the ratio of the IC 50 (Deutsch et al, 1999). The DR is utilized only as one means of comparison of compounds assayed under rigorously maintained experimental conditions: even small variations in the assay conditions can drastically alter the DR value (Rothman et al, 1993;Xu et al, 1995).…”

“…These assays were conducted using rat striatal tissue as previously described (Deutsch et al, 1999). IC 50 values (that concentration of drug which inhibits 50% of specific binding of the radioligand) and Hill coefficients were determined by least-squares nonlinear regression analysis of sigmoidal dose-response curves using the GraphPad Prism (v.2) program (GraphPad Software, Inc., San Diego, CA).…”

“…The effect of test compounds on the accumulation of [ 3 H]DA was determined using a crude synaptosomal preparation of rat striatal tissue that was preincubated for 10 min in the presence of the test compound, then exposed to 30 nM [ 3 H]DA over a 2-min period at 37°C, as described previously (Deutsch et al, 1999 …”