Vol. 301, Issue 2, 527-535, May 2002

Biochemical and Behavioral Characterization of Novel Methylphenidate Analogs

M. M. Schweri, H. M. Deutsch, A.T. Massey¹ and S. G. Holtzman

Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia (M.M.S., A.T.M.); School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia (H.M.D.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (S.G.H.)

As part of a project to develop treatment agents for cocaine abuse, (±)-threo-methylphenidate (TMP) and 11 analogs were characterized biochemically and behaviorally to assess their potential as anti-cocaine medications. The compounds contained aryl and/or nitrogen substitutions, and/or replacement of the ester function by an alcohol or ether. All of the analogs, except for the N-methyl-substituted compounds, showed increased inhibitory potency against ³H-()-2--carbomethoxy-3--(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate ([³H]WIN 35,428) ([³H]WIN) binding to the dopamine transporter, compared with TMP. In general, parallel results were obtained for inhibition of [³H]dopamine ([³H]DA) uptake. Although compounds with N-substitutions were proportionally less potent at blocking DA uptake than WIN binding (compared with the unsubstituted compounds), one such compound that was 6-fold more potent against [³H]WIN binding than [³H]DA uptake did not attenuate inhibition by cocaine of synaptosomal [³H]DA transport. The compounds were significantly less potent in displacing [³H]citalopram binding from the serotonin transporter. In cocaine discrimination studies in rats, all but two of the analogs (both N-substituted) completely generalized with the cocaine stimulus. Robust positive correlations were observed between potency in the drug discrimination assay and activity at the dopamine transporter, but not the serotonin transporter. When tested for their ability to alter cocaine discrimination, four of the analogs (three of which had N-substitutions and shallow dose-response curves as cocaine substitutes) actually enhanced cocaine discrimination, often at combined doses of cocaine and test compound that were inactive when given separately. Taken together, the results suggest that TMP analogs may have potential as substitution therapies for the treatment of cocaine abuse.