Benzamide derivatives as allosteric ligands of the human and rat P2X7 receptor.

Abstract

The P2X7 receptor (P2X7R) is a key player of the purinergic signalling and is widely expressed throughout the body. The involvement of this protein in the regulation of physiological processes and the onset and progression of pathological conditions make the P2X7R a key target for the development of novel pharmacological tools for the treatment of inflammation-related conditions, cancer, and neurological diseases. Here we report the synthesis and biological evaluation of an array of 2-bromo-benzamide derivatives as novel allosteric ligands of the P2X7R. The compounds ability to bind and inhibit the receptor was evaluated with radioligand binding assay at both the human and rat proteins and functional studies at the human P2X7R, stably transfected in HEK293 cells. The affinity was analysed with the aid of molecular modelling studies performed at both receptors. All the compounds showed nanomolar to micromolar affinity for the human P2X7R and a lower ability to bind the rat protein. Inhibitory potency at the human P2X7R ranged from nanomolar to micromolar levels, with one compound showing sub-nanomolar inhibitory potency. These results confirm the 2-bromo-benzamide scaffold as a solid basis for the development of novel P2X7R allosteric ligands.