Design, synthesis and biological evaluation of GPR55 agonists

Abstract

GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesized in a modular fashion to obtain structure-activity relationship information. The general route consisted of coupling a variety of p-aminophenyl sulfonamides to isothiocyanates to form acylthioureas. For the synthesis of a known naphthyl ethyl alcohol motif, route modification led to a shorter and more efficient process. The 22 analogues were analyzed for their ability to serve as agonists at GPR55 and valuable information for both ends of the molecule was ascertained.

Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18

“…However, because we measured β 2 -arrestin recruitment only, which is well described for GPR55, and not β 1 -arrestin recruitment, it cannot be fully excluded at present that the compound might interact with GPR55 when differently assayed. The same applies to a potential bias toward G-protein signaling. − …”

Chemical Transformations of Biomass-Derived C6-Furanic Platform Chemicals for Sustainable Energy Research, Materials Science, and Synthetic Building Blocks

“…Various N -nucleophiles can be subjected to reaction with HMF leading to imines, oximes, and hydrazones . Long-chain N -hydroxyaminocoumarins were used as LC-MS labels for analysis of HMF …”

“…150 It was reported that dithioacetals can be prepared under ambient and solvent-free conditions using zeolites as catalysts. 151 Various N-nucleophiles can be subjected to reaction with HMF leading to imines, 152 oximes, and hydrazones. 153 Longchain N-hydroxyaminocoumarins were used as LC-MS labels for analysis of HMF.…”

Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer's disease?

“…It was initially believed that the endocannabinoid system only contained two target receptors -CB 1 and CB 2 . However, the recently deorphanised GPR55 is now also considered a cannabinoid receptor, given thatin addition to its endogenous activation by lysophosphatidyl inositol (LPI) and N-arachidonyl glycine (NAGly) [30,31] it is activated by a breadth of endo-, phyto-and synthetic cannabinoids [32][33][34][35][36][37]. Interestingly, GPR55 has fairly low sequence homology with both CB 1 (13.5%) and CB 2 (14.4%) [36,38], and lacks the classical cannabinoid binding pocket expressed by CB 1 and CB 2 [39], meaning that it is somewhat of an atypical cannabinoid receptor.…”