Synthesis, biological activity and molecular modeling of new biphenylic carboxamides as potent and selective CB2 receptor ligands

Abstract

The CB2 receptor is a therapeutic target of increasing importance for several diseases, including pain, inflammation, neurodegeneration, cancer and osteoporosis. While several compounds showing CB2-selective agonist or inverse agonist properties have been developed, only few CB2 receptor selective neutral antagonists are actually known. Such type of compounds could be useful to study more in depth the role of the CB2 receptor, because they lack the ability to counteract its "constitutive" activity. Here we describe the synthesis and biological activity of a series of biphenylic carboxamides as a new class of CB2 receptor selective ligands. In binding assays, one of these compounds showed good CB2 receptor affinity and selectivity (Ki = 11.48 nM; Selectivity Index = 130). Furthermore, in functional assays, the same compound showed a very interesting pharmacological profile as CB2 receptor selective neutral antagonist. These results pave the way to further developments, including structural optimization, with the aim to obtain more potent CB2 receptor ligands with this peculiar feature.

Ligand-based homology modelling of the human CB2 receptor SR144528 antagonist binding site: a computational approach to explore the 1,5-diaryl pyrazole scaffold

“…32 The binding cavity reorganization induced by ligand interaction was caused by quite a conformational change of a number of amino acid side chains, belonging to TM3, TM4 and TM5 (volume = 1813 Å 3 ). 32 The binding cavity reorganization induced by ligand interaction was caused by quite a conformational change of a number of amino acid side chains, belonging to TM3, TM4 and TM5 (volume = 1813 Å 3 ).…”

“…The most probable interaction site of the LBHM-driven model, as identified by the MOE Site finder module, included most of the reported residues involved in the antagonist binding (see the mutagenesis data). 32 The binding cavity reorganization induced by ligand interaction was caused by quite a conformational change of a number of amino acid side chains, belonging to TM3, TM4 and TM5 (volume = 1813 Å 3 ). More in detail, the antagonist SR144528 binding site included the following residues: (i) L107, I110, G111, T114, M115 and T118 in TM3; (ii) L160, S161, L163, V164, S165, P168, L169 in TM4 and (iii) Y190, L191, W194, L195, F197, I198, F202 in TM5.…”

“…27,28 Concerning this issue, during the past years we published a number of studies performed as LB and SB analyses of CB 1 antagonists and of several series of CB 2 agonists, without exploring the CB 2 antagonist activity. 24,32,33 Thus, in the present work, a model of the human CB 2 receptor (hCB 2 ) was developed by a LB homology modelling (LBHM), in order to carefully explore the pyrazole antagonist-CB 2 receptor interactions. 24,32,33 Thus, in the present work, a model of the human CB 2 receptor (hCB 2 ) was developed by a LB homology modelling (LBHM), in order to carefully explore the pyrazole antagonist-CB 2 receptor interactions.…”

“…[29][30][31] In this context, up to now only a few number of SB molecular models of the CB 2 receptor in complex with the antagonist compound were built and evaluated, leading sometimes to contradictory results. 24,32,33 Thus, in the present work, a model of the human CB 2 receptor (hCB 2 ) was developed by a LB homology modelling (LBHM), in order to carefully explore the pyrazole antagonist-CB 2 receptor interactions. The LBHM presented here was performed taking into account the antagonist SR144528 structural features and then evaluating the model reliability through a comparison with the mutagenesis data reported by Gouldson.…”

Structure-Activity Relationship of Cannabis Derived Compounds for the Treatment of Neuronal Activity-Related Diseases

“…SAR studies carried out on biphenylic carboxamides showed once more that a large cycloalkyl ring (cycloheptyl) on the carboxamide function improves affinity and selectivity for the CB2 receptor, while substituents in C-(5) and C-(4′) are mainly responsible for the activity profile [ 104 , 105 ].…”