Synthesis, pharmacological evaluation and docking studies of pyrrole structure-based CB<inf>2</inf> receptor antagonists

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 [35S]-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.GM acknowledges Regione Autonoma della Sardegna for economic support (grant n. CRP-26417, LR n. 7/2007 and INNOVA.REPOR FESR 2007-2013). PM is recipient of a CSIC fellowship JAEPre- 2010-01119 from Junta para la Ampliacion de Estudios cofinanced by FSE. MGA was recipient of a postdoctoral fellowship from the PICATA Program, CEI-Moncloa. NJ thanks the Spanish Ministry of Economy and Competitivity for the grant SAF2012- 40075, and with JFR the “Programa de Biomedicina, Comunidad de Madrid” (S2011/BMD-2308).Peer Reviewe