(+)-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 σ<INF>1</INF>, σ<INF>2</INF>, and phencyclidine (PCP) sites and opioid, muscarinic (M<INF>2</INF>), dopamine (D<INF>2</INF>), and serotonin (5-HT<INF>2</INF>) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds <BO>8c</BO>−<BO>11c</BO> displayed high affinities for σ<INF>1</INF> sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (<BO>1a</BO>−<BO>6a</BO>) with high affinity and selectivity for σ<INF>1</INF> binding sites. Compounds <BO>1a</BO>−<BO>5a </BO>were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound <BO>1a</BO> and <BO>2a </BO>as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds <BO>3a</BO>−<BO>5a</BO> 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 σ<INF>1</INF> ligands which might prove useful to unveil the functional role of σ<INF>1</INF> sites.