title: (+)-cis-N-ethyleneamino-N-normetazocine derivatives. Novel and selective sigma ligands with antagonist properties.
abstract: A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, 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 sigma1 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 sigma1 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 sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.
authors.affiliation: Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria, 6, 95125 Catania, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ronsisvalle
authors.forename: A
authors.initials: A
authors.lastname: Marrazzo
authors.forename: O
authors.initials: O
authors.lastname: Prezzavento
authors.forename: L
authors.initials: L
authors.lastname: Pasquinucci
authors.forename: F
authors.initials: F
authors.lastname: Vittorio
authors.forename: V
authors.initials: V
authors.lastname: Pittalà
authors.forename: M S
authors.initials: MS
authors.lastname: Pappalardo
authors.forename: S
authors.initials: S
authors.lastname: Cacciaguerra
authors.forename: S
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D043585:Receptor, Muscarinic M2; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D001575:Benzomorphans; D008024:Ligands; D043585:Receptor, Muscarinic M2; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D011957:Receptors, Opioid; D011985:Receptors, Serotonin; D017480:Receptors, sigma