1-[1-(2-BENZO[B]THIOPHENEYL)CYCLOHEXYL]PIPERIDINE HYDROCHLORIDE (BTCP) YIELDS 2 ACTIVE PRIMARY METABOLITES IN-VITRO - SYNTHESIS, IDENTIFICATION FROM RAT-LIVER MICROSOME EXTRACTS, AND AFFINITY FOR THE NEURONAL DOPAMINE TRANSPORTER

1-[1-(2-Benzo[b]thiopheneyl)cyclohexyl]piperidine hydrochloride (BTCP, 1) and cocaine bind to the neuronal dopamine transporter to inhibit d opamine (DA)reuptake. However, on chronic administration, cocaine prod uces sensitization, but 1 produces tolerance. Because metabolites of 1 might be responsible for some of its pharmacological properties, we h ave identified the primary metabolites of 1 produced by rat liver micr osomes and determined their affinities for the DA transporter. Five mo nohydroxylated derivatives (3, 5, 9, 10, 14) and two degradation compo unds (15, 16) were identified as metabolites through comparison with s ynthetic standards in HPLC and GC systems. Standards were obtained uti lizing synthetic schemes previously used for the synthesis of phencycl idine metabolites. In vitro, two compounds (3, pi) showed a high affin ity for the DA transporter. These active metabolites might be importan t in the pharmacology of 1.