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Pure Appl. Chem., 2001, Vol. 73, No. 9, pp. 1499-1509

Opioid and sigma receptor studies. New developments in the design of selective sigma ligands

Giuseppe Ronsisvalle1, Agostino Marrazzo1, Orazio Prezzavento1, Alfredo Cagnotto2, Tiziana Mennini2, Carmela Parenti1 and Giovanna M. Scoto1

1 Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria, 6, 95125 Catania
2 Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy

Abstract: New racemic and chiral methyl 2-{[4-(4-chlorophenyl)-4-hydroxypiperi-din-1-yl]methyl}-1-phenylcyclopropanecarboxylate derivatives were synthesized in order to obtain sigma ligands with increased affinity and selectivity compared to (+)-MPCB and haloperidol. The cis-(±)-7 racemic mixture showed a better binding affinity and selectivity than the (±)-8 trans isomers. Between the two cis enantiomers, (+)-7, with configuration (1R,2S), showed a very high affinity and the best selectivity for s1. All compounds synthesized (7­9) showed a reduced or negligible affinity for opioid and dopaminergic D1 and D2 receptors. Nociceptive in vivo test confirms that (+)-7 (namely MR200), such as non-selective antagonist haloperidol, increased the analgesic effect induced by the k opioid selective ligand U50,488H and reversed the inhibiting effect of (+)-pentazocine on analgesia.