Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands

Abstract

Recent developments indicate that CB2 receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB2 receptor and little affinity for the CB1 receptor. This review will discuss structure-activity relations at both receptors for classical cannabinoids and cannabimimetic indoles. Examples of CB2 selective ligands from both classes of compounds are presented and the structural features leading to selectivity are described. Two approaches, receptor mutations and molecular modelling, have been employed to investigate the interaction of ligands with both cannabinoid receptors. These results obtained from these techniques are discussed.

Here Today, Gone Tomorrow…and Back Again? A Review of Herbal Marijuana Alternatives (K2, Spice), Synthetic Cathinones (Bath Salts), Kratom, Salvia divinorum, Methoxetamine, and Piperazines

“…These compounds represent a small fraction of the many available synthetics designed by pharmaceutical companies and researchers exploring cannabinoid receptor-ligand binding. Since the 1960s, the pharmaceutical and research communities have been in search of cannabinoid receptor agonists with the analgesic and antiinflammatory properties of tetrahydrocannabinol (Δ9-THC), without the psychotropic side effects [7][8][9][10][11][12]. The synthetic cannabinoids developed over this time have led to a better understanding of the cannabinoid receptors (CB 1 and CB 2 ) [3,[13][14][15][16][17][18][19][20][21][22].…”

Cannabinoid CB2 Receptors in Health and Disease

“…There have been extensive reviews describing the discovery and characterization of CB 2 ligands that may act as agonists, antagonists or inverse agonists [24,[55][56][57]. An interesting concept applied to this receptor is that of protean agonism.…”

“…There has been less attention to other classes of CB 2 receptor ligands, but the discovery that 6-methoxy-N-alkyl isatin acylhydrazone derivatives are novel inverse agonists that were developed based on modelling the structure of the 2 -adrenergic receptor offers promise of further new developments in this area [66]. The now classical antagonists (inverse agonists) SR144528 and AM630 remain the mainstay of tools for studies in this area [6,[55][56][57].…”

GC–MS analysis of the regioisomeric methoxy- and methyl-benzoyl-1-pentylindoles: Isomeric synthetic cannabinoids

“…A number of structure-activity studies have been published with respect to the activity of 3-acyl-1-alkylindole derivatives at the cannabinoid-1 (CB-1) receptor, the receptor that mediates the cannabis-like psychologic effects of these drugs [1][2][3][4]. These studies have focused primarily on modification of the substituents on positions 1, 2 and 3 on the indole nucleus.…”