CB2 Receptor Ligands

Abstract

The CB(1) receptor is found principally in the central nervous system and is responsible for the overt physiological effects of cannabinoids. In contrast, the CB(2) receptor is expressed primarily in the immune system and is responsible for few, if any, obvious behavioral effects. Although many cannabinoid receptor ligands show little, or at best modest, selectivity for either receptor, a number of synthetic compounds are known which have significant selectivity for the CB(2) receptor. These include cannabimimetic indoles, such as 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) and 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpho-lino]ethyl)-5-methoxyindole (L768242), both of which have good affinity for the CB(2) receptor, but weak affinity for the CB(1) receptor. Efforts have been made to develop structure-activity relationships (SAR) at CB(2) for cannabimimetic indoles, but with limited success. Several derivatives of traditional dibenzopyran based cannabinoids have also been found to have significant selectivity for the CB(2) receptor. These include 1-methoxy-Delta(8)-THC derivatives, 1-methoxy-Delta(8)-THC-DMH (L759633), 1-methoxy-Delta(9(11))-THC-DMH (L759656), and 1-methoxy-3-(1',1'-dimethylhexyl)-Delta(8)-THC (JWH-229), plus a number of 1-deoxy-Delta(8)-THC analogues. In particular, 1-deoxy-3-(1',1'-dimethylbutyl)-Delta(8)-THC (JWH-133) shows two hundred-fold selectivity for the CB(2) receptor. Very recently several compounds belonging to other structural groups have also shown selectivity for the CB(2) receptor. This review will describe the current status of the results of these studies and discuss the SAR for these classes of ligands.

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

“…Other mice received WIN 55,212-2, (10 g /day) together with the peptides. Mice receiving only A [25][26][27][28][29][30][31][32][33][34][35] showed significantly reduced levels of the neuronal proteins calbindin and -tubulin, matching similar findings in human Alzheimer's brains. These mice also showed a marked inability to improve on a Morris water maze test compared with controls.…”

“…Mice were subject to intracerebroventricular daily injections of A [25][26][27][28][29][30][31][32][33][34][35] or a control peptide for 7 days. Other mice received WIN 55,212-2, (10 g /day) together with the peptides.…”

“…This is currently an area of intense activity. There are currently a number of potent and moderately selective CB2 agonists such as JWH-015 and JWH-133 [28], and AM1421 [79]. Although extremely useful for experimental analysis of CB receptor function, these compounds are insufficiently selective for preclinical testing.…”

Cannabinoids and Neuropathic Pain

“…JWH-133 is another potent indole that is part of a family of compounds named after their discoverer, JW Huffman, and shows a high degree of selectivity (200-fold) for CB2 (Huffman, 2005).…”

GPCR Structure‐Based Virtual Screening Approach for CB2 Antagonist Search.

“…[20][21][22][23][24][25] The advances made in the medicinal chemistry of arylpyrazoles as cannabinergic ligands have been highlighted in recent review articles. 26,27 Structure-activity relationship (SAR) studies were also conducted to gain further insight into quantitative 28,29 and qualitative 30,31 SAR models for the arylpyrazoles affinities on cannabinoid receptors. Furthermore, positive results in the clinical trials of SR141716A have successfully enabled it to become a new drug, named Rimonabant (Acomplia, Sanofi-Synthelabo), for the management of obesity, smoking cessation, and cardimetabolic risk factor 32 in Britain.…”