Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators.

Paula Morales,Chanté Muller,Patricia H Reggio,Nadine Jagerovic

doi:10.3389/fmolb.2022.841190

Abstract

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.

Highlights

The expression of cannabinoid receptor type 2 (CB2) is detected in the central nervous system (CNS) under stressful conditions such as cytotoxic and neuroinflammatory injuries within the brainstem, microglia, and astrocytes, suggesting CB2 an interesting target for neuroprotection (Navarro et al, 2016)
Three-dimensional crystal and cryo-EM structures of G-protein-coupled receptor (GPCR) and TRP channels are being resolved at a rapid pace in the last years
The endocannabinoid system (ECS) is composed by a variety of receptors including GPCRs, TRP channels, nuclear receptors such as the PPARs (Morales et al, 2017b)

Summary

Introduction

Well documented pharmacological evidence supports functional crosstalk between the endocannabinoid system (ECS) and the endovanilloid system (EVS) (Di Marzo et al, 2002; Lastres-Becker et al, 2003; Morgese et al, 2007; Avraham et al, 2010; Chávez et al, 2010; Adamczyk et al, 2012; Arnold et al, 2012; Lowin and Straub, 2015; Rossi et al, 2015; Malek and Starowicz, 2016; Assimakopoulou et al, 2017; Bellini et al, 2017; Zhang et al, 2017; Punzo et al, 2018; Bhatta et al, 2019; Wi et al, 2020). CB2R is a G-protein-coupled receptor (GPCR) mainly present in the immune cells where they are expressed in lymphocytes, natural killer cells, macrophages, and neutrophils (Cécyre et al, 2020). They are an attractive target for the treatment of inflammatory processes. In animal models of chronic inflammation, CB2 agonists lead to beneficial outcomes for diverse pain managements such as neuropathic, osteoarthritic, postoperative, and human immunodeficiency

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