title: 1,2-Dihydro-2-oxopyridine-3-carboxamides: the C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor.
abstract: The relevance of CB2R-mediated therapeutic effects is well-known for the treatment of inflammatory and neuropathic pain and neurodegenerative disorders. In our search for new cannabinoid receptor modulators, we report the optimization of a series of 1,2-dihydro-2-oxopyridine-3-carboxamide derivatives as CB2R ligands. In particular, N-cycloheptyl-5-(4-methoxyphenyl)-1-(4-fluorobenzyl)-pyridin-2(1H)-on-3-carboxamide (17) showed high CB2R affinity (K(i) = 1.0 nM), accompanied by interesting K(i)(CB1R)/K(i)(CB2R) selectivity ratio (SI = 43.4). Compound 17 was also identified as a potent CB2R neutral antagonist/weak partial inverse agonist. Finally we found that the functionality activity of the series of 1,2-dihydro-2-oxopyridine is controlled by the presence of a substituent in position 5 of the heterocyclic nucleus. In fact when the hydrogen atom in position 5 of the unsubstituted compound 1 was replaced with a phenyl group (compound 18) the CB2R activity was shifted from agonism to inverse agonism whereas the introduction in the same position of p-methoxyphenyl group lead to compound 17 which showed a behavior as CB2R neutral antagonist/weak partial inverse agonist.
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Valentina
authors: V
authors: Lucchesi
authors: University of Eastern Finland, Faculty of Health Sciences, School of Pharmacy, PO Box 1627, 70211 Kuopio, Finland; University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland. Electronic address: Teija.Parkkari@uef.fi.
authors: Teija
authors: T
authors: Parkkari
authors: University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland.
authors: Juha R
authors: JR
authors: Savinainen
authors: Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84084 Fisciano, SA, Italy.
authors: Anna Maria
authors: AM
authors: Malfitano
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Marco
authors: M
authors: Allarà
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Simone
authors: S
authors: Bertini
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Francesca
authors: F
authors: Castelli
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Sara
authors: S
authors: Del Carlo
authors: Institute of Endocrinology and Experimental Oncology, IEOS, CNR, Naples, Italy.
authors: Chiara
authors: C
authors: Laezza
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Alessia
authors: A
authors: Ligresti
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Giuseppe
authors: G
authors: Saccomanni
authors: Dipartimento di Scienze Farmaceutiche, Università di Salerno, 84084 Fisciano, SA, Italy.
authors: Maurizio
authors: M
authors: Bifulco
authors: Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Marco
authors: M
authors: Macchia
authors: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: manera@farm.unipi.it.
authors: Clementina
authors: C
authors: Manera
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D011725:Pyridines; D043885:Receptor, Cannabinoid, CB2; C023666:pyridine
keywords: CB1 receptor; CB2 receptor; CB2 receptor inverse agonist; CB2 receptor neutral antagonist; Cannabinoid