(-CIS-N-ETHYLENEAMINO-N-NORMETAZOCINE DERIVATIVES - NOVEL AND SELECTIVE SIGMA-LIGANDS WITH ANTAGONIST PROPERTIES())

A series of (+)-cis-N-normetazocine derivatives has been described, an d their affinities for sigma(1), sigma(2), and phencyclidine (PCP) sit es and opioid, muscarinic (M-2), dopamine (D-2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a sub stituted ethylamino spacer was investigated. Compounds 8c-11c displaye d high affinities for sigma(1) sites and for opioid receptors. Substit ution of the second basic nitrogen either with alkyl or cycloalkyl sub stituents give compounds (1a-6a) with high affinity and selectivity fo r sigma(1) binding sites. Compounds 1a-5a were further characterized i n vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-relate d manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior indu ced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma(1) ligands which mi ght prove useful to unveil the functional role of sigma(1) sites.