title: Tricyclic pyrazoles. Part 1: synthesis and biological evaluation of novel 1,4-dihydroindeno[1,2-c]pyrazol-based ligands for CB1and CB2 cannabinoid receptors.
abstract: Cannabinoids receptors, cellular elements of the endocannabinoid system, have been the focus of extensive studies because of their potential functional role in several important physiological and pathological processes. To further evaluate the properties of CB receptors, especially CB(1) and CB(2) subtypes, we have designed, using SR141716A as a benchmark, a new series of rigid 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides. Compounds 1 were synthesized from substituted 1-aryl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acids and requisite amines. The various analogues were assayed for binding both to the brain and peripheral cannabinoid receptors (CB(1) and CB(2)). Seven of the new compounds displayed very high in vitro CB(2) binding affinities, especially 1a, 1b, 1c, 1e, 1g, 1h and 1j which showed K(i) values of 0.34, 0.225, 0.27, 0.23, 0.385, 0.037 and 0.9 nM, respectively. Compounds 1a, 1b, 1c and 1h showed the highest selectivity for CB(2) receptor with K(i)(CB(1)) to K(i)(CB(2)) ratios of 6029, 5635, 5814 and 9810, respectively. Noticeably, 1h exhibited the highest affinity and selectivity for CB(2) receptors.
authors.affiliation: Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Jean Mario
authors.initials: JM
authors.lastname: Mussinu
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Mulè
authors.forename: Amedeo
authors.initials: A
authors.lastname: Pau
authors.forename: Mauro A M
authors.initials: MA
authors.lastname: Carai
authors.forename: Giovanni
authors.initials: G
authors.lastname: Loriga
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.forename: Gérard A
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry; D063385:Cannabinoid Receptor Modulators; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D000588:Amines; D001555:Benzene Derivatives; D063385:Cannabinoid Receptor Modulators; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014316:Tritium; D000077285:Rimonabant