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

New racemic and chiral methyl 2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-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 σ1. All compounds synthesized (7-9) 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 κ opioid selective ligand U50,488H and reversed the inhibiting effect of (+)-pentazocine on analgesia.