title: Evaluation of N-substituent structural variations in opioid receptor profile of LP1.
abstract: The benzomorphan scaffold has great potential as lead structure and the nature of the N-substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N-substituent (9-15). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity (Ki(MOR)=38±4nM) displaying good selectivity versus DOR and KOR. In the electrically stimulated GPI, compound 9 was inactive as agonist but produced an antagonist potency value (pA2) of 8.6 in presence of MOR agonist DAMGO. Moreover, subcutaneously administered it antagonized the antinociceptive effects of morphine with an AD50=2.0mg/kg in mouse-tail flick test. Modeling studies on MOR revealed that compound 9 fit very well in the binding pocket but in a different way in respect to the agonist LP1. Probably the replacement of its N-substituent on the III, IV and V TM domains reflects an antagonist behavior. Therefore, compound 9 could represent a potential lead to further develop antagonists as valid therapeutic agents and useful pharmacological tools to study opioid receptor function.
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Pasquinucci
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: rita.turnaturi@tiscali.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Turnaturi
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Aricò
authors.affiliation: Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Center for Scientific Research 'Demokritos', Ag. Paraskevi 15310, Athens, Greece.
authors.forename: Paschalina
authors.initials: P
authors.lastname: Pallaki
authors.affiliation: Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Center for Scientific Research 'Demokritos', Ag. Paraskevi 15310, Athens, Greece.
authors.forename: Zafiroula
authors.initials: Z
authors.lastname: Georgoussi
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ronsisvalle
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001575:Benzomorphans / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C569975:3-((2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl)-N-phenylpropanamide; D000701:Analgesics, Opioid; D001575:Benzomorphans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
keywords: 6,7-Benzomorhan scaffold; GPI and MVD assays; Modeling studies; Mu opioid receptor; Radioligand competition-binding assay; Tail-flick test