title: A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.
abstract: 8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed.
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010, Pula, CA, Italy; Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK; KemoTech Srl, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy. Electronic address: paolo.lazzari@kemotech.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010, Pula, CA, Italy; Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Distinto
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010, Pula, CA, Italy; Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Manca
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada.
authors.forename: Gemma
authors.initials: G
authors.lastname: Baillie
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100, Sassari, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.affiliation: Neuroscienze PharmaNess S.c.a r.l., Edificio 5, Loc. Piscinamanna, 09010, Pula, CA, Italy; Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pira
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Lab. Genetica, Università di Cagliari, Via T.Fiorelli 1, 09126 Cagliari, CA, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falzoi
authors.affiliation: KemoTech Srl, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy; C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Sani
authors.affiliation: Instituto de Química Médica, CSIC, C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Morales
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ross
authors.affiliation: Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK; C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, 20131 Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanda
authors.affiliation: Instituto de Química Médica, CSIC, C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100, Sassari, Italy.
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D055808:Drug Discovery; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C000614172:8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo(6,7)cyclohepta(1,2-c)pyrazole-3-carboxamide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1
keywords: 8-Chloro-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide; CB(1) receptor ligands; Cannabinoid receptor binding assays; Endocannabinoid system (ECS); cannabinoids