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 CB 2 receptor antagonist N -fenchyl-5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-1 H -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 ( K i in the low nM range) and selectivity for the CB 2 receptor and both resulted to be antagonists/inverse agonists in [ 35 S]-GTPγS binding analysis and in an in vitro CB 2 receptor bioassay. Cannabinoid receptor binding data of the series allowed identifying steric constraints within the CB 2 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 CB 2 receptor inactive state model.