Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction

In order to make new analogs of the dopamine (DA) uptake inhibitor methylph enidate, a synthetic methodology based on the Blaise reaction was developed . The reaction between alpha -bromophenylacetic acid esters, zinc and alpha -cyano-omega -mesylates gave stable primary enamines. After reduction of t he enamines with cyanoborohydride, the amines could be cyclized to methylph enidate analogs in which the amine ring size and aromatic ring were varied. These compounds were tested for inhibitory potency against [(3)2H]WIN 35,4 28 binding to the cocaine recognition site and [H-3]DA uptake using rat str iatal tissue. When the heterocyclic ring size was varied, the six-membered ring of methylphenidate appeared to be the optimum ring size. When the aryl ring was varied the 4-trifluoromethylphenyl analog was less potent than me thylphenidate, the beta -naphthyl congener was considerably more potent. wh ereas the alpha -naphthyl congener was less potent. Most of the compounds t ested had ratios of uptake to binding inhibition (discrimination ratio), th at were similar to cocaine and were therefore not lead compounds for the de velopment of cocaine antagonists. (C) 2001 Editions scientifiques at medica les Elsevier SAS.