title: Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB2 receptor antagonists.
abstract: During the last years, there has been a continuous interest in the development of cannabinoid receptor ligands that may serve as therapeutic agents and/or as experimental tools. This prompted us to design and synthesize analogues of the CB2 receptor antagonist N-fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1H-pyrazole-3-carboxamide (SR144528). The structural modifications involved the bioisosteric replacement of the pyrazole ring by a pyrrole ring and variations on the amine carbamoyl substituents. Two of these compounds, the fenchyl pyrrole analogue 6 and the myrtanyl derivative 10, showed high affinity (Ki in the low nM range) and selectivity for the CB2 receptor and both resulted to be antagonists/inverse agonists in [(35)S]-GTPγS binding analysis and in an in vitro CB2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB2 binding pocket using a study of Van der Waals' volume maps. Glide docking studies revealed that all docked compounds bind in the same region of the CB2 receptor inactive state model.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Ragusa
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Cañas
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Morales
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Deligia
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pazos
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Pinna
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Goya
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: nadine@iqm.csic.es.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Campus de Excelencia Internacional (CEI-Moncloa), Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. Electronic address: moisesgar@med.ucm.es.
authors.forename: Moisés
authors.initials: M
authors.lastname: García-Arencibia
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy. Electronic address: muri@uniss.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
mesh_terms: D001892:Camphanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001892:Camphanes; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528
keywords: Bioisosterism; CB(2) antagonism; Cannabinoid receptors; Docking studies; Synthesis