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

• Published in: Journal of medicinal chemistry 1999-03, Vol.42 (5), p.882-895
• Main Authors: Deutsch, Howard M, Collard, David M, Zhang, Liang, Burnham, Kikue S, Deshpande, Abhay K, Holtzman, Stephan G, Schweri, Margaret M
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - metabolism; Bridged Bicyclo Compounds - pharmacology; Cocaine - analogs & derivatives; Cocaine - metabolism; Cocaine-Related Disorders - drug therapy; Discrimination Learning - drug effects; Dopamine - metabolism; Dopamine Uptake Inhibitors - chemical synthesis; Dopamine Uptake Inhibitors - chemistry; Dopamine Uptake Inhibitors - metabolism; Dopamine Uptake Inhibitors - pharmacology; Drug addictions; In Vitro Techniques; Male; Medical sciences; Models, Molecular; Neostriatum - metabolism; Neostriatum - ultrastructure; Protein Binding; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Synaptosomes - metabolism; Toxicology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980566m

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 n H 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.