Synthesis and Pharmacological Activity of Potential Cocaine Antagonists.2. Structure-Activity Relationship Studies of Piperidine Ring-Substituted Methylphenidate Analogs

As part of a program to develop medications which can preferentially block the binding of cocaine to the dopamine transporter, yet spare dopamine, a new series of N-substituted methylphenidate derivatives was synthesized and evaluated for inhibitory potency in [3H] WIN 35,428 binding and [3H] dopamine uptake assays using rat striatal tissue. Structure-activity relationships studies associated these as potential cocaine antagonists were investigated. This series of methylphenidate analogs was developed by introducing various alkyl and aryl groups on the piperidine nitrogen. Preliminary pharmacological studies indicated that for the N-aryl group, the best activity is obtained when the piperidine nitrogen atom was alkylated with 4-chlorobenzyl group. The N-(4-chlorobenzyl) methylphenidate analog (1d) is 2-fold more potent than methylphenidate in [3H] WIN 35,428 binding and about 1.5-fold more potent in [3H] dopamine uptake assays Furthermore, compound 1d is 2-fold more potent than methylphenidate in [3H] WIN 35,428 binding and about 1.5-fold more potent in [3H] dopamine uptake assays. Compound 1c, although significantly less potent than methylphenidate in both assays, has the highest DR (8.2) in the series. Large N-aryl-substituted analogs were significantly less active than the corresponding N-benzyl analog. The data provide further evidence that N-alkylation changes aromatic ring SAR and the utility of methylphenidate derivatives in the development of site-directed treatment agents as partial agonists or antagonists of cocaine.