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

Ronsisvalle, Giuseppe; Marrazzo, Agostino; Prezzavento, Orazio; Cagnotto, Alfredo; Mennini, Tiziana; Parenti, Carmela; Scoto, Giovanna M.

doi:10.1351/pac200173091499

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

http://dx.doi.org/10.1351/pac200173091499

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.