Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders

Abstract

Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson's disease, Huntington's chorea, cerebellar ataxia, amyotrohic lateral sclerosis). Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration. Medicinal chemistry approaches are now engaged to develop imaging tools to map receptors in the living human brain, to develop more efficacious agonists, and to investigate the possibility to develop allosteric modulators.

Keywords: GPCR; M0/M1/M2 phenotype; amyotrophic lateral sclerosis; astroglia; heteromer; microglia; neuroprotection; neurorestoration.

Figure 1

Chemical structure of Δ⁹-THC, nabilone, and the CB₂R ligands: JWH133, 0-1966, AEA, BCP, SMM-189, PM226, 1-butyl-3-[(cyclohexylamino)methylidene]-8-methylquinoline-2,4(1H,3H)-dione, [¹¹C]NE40, [¹¹C]KD2, [¹¹C]RS-016, 2-{2-chloro-[5-(4-[¹⁸F]-d₂-methoxy)-6-(4-fluorophenethylamino)-1,3,5-triazin-2-yl]phenyl}propan-2-ol.

Figure 2

(A). Expression of CB₂Rs in different neural cell types and how receptor activation may impact on cell-specific functions. (B) Cellular events that explain the therapeutic possibilities for ligands that target CB₂Rs, which are upregulated in activated glial cells.