(+)-cis-N-Ethyleneamino-N-normetazocine Derivatives. Novel and Selective σ Ligands with Antagonist Properties

A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for σ1, σ2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c−11c displayed high affinities for σ1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a−6a) with high affinity and selectivity for σ1 binding sites. Compounds 1a−5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a−5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective σ1 ligands which might prove useful to unveil the functional role of σ1 sites.