Chain Substituted Cannabilactones with Selectivity for the CB2 Cannabinoid Receptor.

Shakiru O Alapafuja,Thanh C Ho,Fei Tong,Spyros P Nikas,Alexandros Makriyannis,Othman Benchama

doi:10.3390/molecules24193559

Abstract

In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1′-gem-dimethyl group with the bulkier cyclopentyl ring, and, we also probed the chain’s length and terminal carbon substitution with bromo or cyano groups. One of the analogs synthesized namely 6-[1-(1,9-dihydroxy-6-oxo-6H-benzo[c]chromen-3-yl) cyclopentyl] hexanenitrile (AM4346) has very high affinity (Ki = 4.9 nM) for the mouse CB2 receptor (mCB2) and 131-fold selectivity for that target over the rat CB1 (rCB1). The species difference in the affinities of AM4346 between the mouse (m) and the human (h) CB2 receptors is reduced when compared to our first-generation cannabilactones. In the cyclase assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC50 = 3.7 ± 1.5 nM, E(max) = 89%). We have also extended our structure-activity relationship (SAR) studies to include biphenyl synthetic intermediates that mimic the structure of the phytocannabinoid cannabinodiol.

Highlights

The two G-protein coupled receptors (GPCRs) termed cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are principal components of the endocannabinoid biosignaling system and molecular targets for the psychoactive constituent of cannabis ∆9 -tetrahydrocannabinol (∆9 -THC) [1,2,3]
The CB2 receptors are detectable at very low levels in brain and they are expressed predominantly in immune cells and in the periphery [8]
The species difference in the affinities of AM4346 between the mouse and the human CB2 receptors is reduced when compared to our first-generation compound AM1714, while AM4346 is endowed with enhanced polarity due to the presence of the cyano group

Summary

Introduction

The two G-protein coupled receptors (GPCRs) termed cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are principal components of the endocannabinoid biosignaling system and molecular targets for the psychoactive constituent of cannabis ∆9 -tetrahydrocannabinol (∆9 -THC) [1,2,3]. The CB1 receptor retains a high (≥97%) degree of amino acid sequence identity across mouse, rat, and human [4]. The human CB2 receptor displays only 82% and 81% amino acid identity with mouse [5] and rat [6] respectively. The CB1 receptor was found to be localized primarily in the brain and it is one of the most abundant GPCRs in the central nervous system (CNS) [4]. This receptor is found in peripheral tissues and organs [7]. Collaborative efforts, including our laboratory, have led to the first crystal structures of the agonist and antagonist bound human CB1, while recently we published the first crystal structure of the Molecules 2019, 24, 3559; doi:10.3390/molecules24193559 www.mdpi.com/journal/molecules

Methods

Results

Conclusion