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
1Department of Pharmaceutical Sciences, University
of Catania, Viale Andrea Doria, 6, 95125 Catania; 2Department 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.
*Plenary lecture presented at the Hungarian-German-Italian-Polish
Joint Meeting on Medicinal Chemistry, Budapest, Hungary, 2 6 September
2001. Other presentations are published in this issue, pp.
1387-1509.
# Corresponding author.
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