Synthesis and pharmacology of site-specific cocaine abuse treatment agents: The role of the phenyl group in highly modified methylphenidate analogs as dopamine uptake inhibitors

A series of modified methylphenidate derivatives was synthesized and tested for inhibitory potency in [H-3]WIN 35,428 binding and [H-3]dopamine uptake assays using rat striatal tissue. In these compounds the role of the pheny l ring was investigated by its removal from the position adjacent to the es ter function. The des-phenyl analogs were then subsequently modified by rei ntroduction of the phenyl ring in the form of N-benzyl, N-(2-phenylethyl) o r N-(3-phenylpropyl). The des-phenyl analogs (la-lc) had no significant aff inity for the [H-3]WIN 35,428 binding site and almost no ability to inhibit [H-3]dopamine uptake, indicating the primary importance of the phenyl grou p. The N-benzyl analogs 2a-2c all had very low affinity, with IC50 values a gainst [H-3]WIN 35,428 binding in the range of 40-100 mu M. Interestingly, among the N-(2-phenylethyl) analogs, the one with the carboxymethyl group i n the 2-position (3a) (like methylphenidate) was much more potent (IC50=2.2 4 mu M) than the analogs with the ester group in the 3- or 4-positions (3b and 3c, IC50 values of 27.1 and 25.4 mu M, respectively). A derivative of 3 a, with 3,4-dichloro substituents (4a), was less potent than the parent com pound. The N-(3-phenylpropyl) compound 5a was also less potent than 3a. Alt hough compound 3a is only some 27-fold less potent than methylphenidate, it appears that its phenyl group is not interacting with the normal aromatic ring binding region of the dopamine transporter.