Synthesis and Pharmacology of Ester Modified (+/-)-threo-Methylphenidate Analogs

INTRODUCTION The research described here is a continuation of an ongoing project whose aim is the synthesis and characterization of derivatives of (±)-threo -methylphenidate (TMP; Ritalin) with potential in the treatment of cocaine (COC) abuse 1, 2, 3, 4, 5, 6, 7 . The reinforcing and stimulant effects of COC are thought to be due, at least in part, to the drug’s ability to block dopamine (DA) re-uptake by binding to a stimulant binding site on the DA transporter located at the DA nerve terminal 8, . TMP also binds to this site, as identified using the radioligand H-WIN 35, 428 (WIN) . The premise of this work is that modification of the TMP molecule may result in one of two possible modes of pharmacotherapies for use in the treatment of COC abuse: (1) a classic cocaine antagonist which will block the binding of cocaine to the DA transporter, but have no intrinsic effect on the uptake of DA, or (2) a long-acting cocaine agonist/partial agonist which can be administered as a cocaine substitute with less reinforcing properties, analogous to the use of methadone for the treatment of heroin addiction.