title: Evaluation of N-substitution in 6,7-benzomorphan compounds.
abstract: 6,7-benzomorphan derivatives, exhibiting different mu, delta, and kappa receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2'-hydroxy-6,7-benzomorphan derivatives (12-22). Data obtained by competition binding assays showed that the mu opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for delta receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to kappa receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high mu affinity (Ki=0.83 nM), good delta affinity (Ki=29 nM) and low affinity for the kappa receptor (Ki=110 nM), with a selectivity ratio delta/mu and kappa/mu of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a mu/delta agonist profile, with IC50 values of 4.8 and 12 nM at the mu and delta receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50=2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a mu/delta agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects.
authors.affiliation: Department of Pharmaceutical Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. lpasquin@unict.it
authors.forename: Lorella
authors.initials: L
authors.lastname: Pasquinucci
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Emanuele
authors.initials: E
authors.lastname: Amata
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
authors.forename: Zafiroula
authors.initials: Z
authors.lastname: Georgoussi
authors.forename: Danai-Dionysia
authors.initials: DD
authors.lastname: Fourla
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Scoto
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Aricò
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*
chemical_list: D000700:Analgesics; D001575:Benzomorphans; D011957:Receptors, Opioid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases