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    • There is no doubt that GPR is

    2021-10-09

    There is no doubt that GPR55 is a LPI receptor; however, we should re-consider whether or not GPR55 is in fact another cannabinoid receptor. The pharmacologies of the GPR55 and CB1 receptors are complicated; CB1 inverse agonist/antagonists SR141716A (rimonabant) and AM251 were shown to be potent agonists for GPR55 [58], while the CB1 agonist CP55940 was an antagonist/partial agonist for GPR55 [59]. Cannabinoid compounds can act on GPR55, but exhibited reverse effects between the GPR55 and CB1 receptors. The CB1 inverse agonist/antagonist SR141716A (rimonabant) was examined as a potential drug for anti-obesity in a clinical trial; however, adverse effects were observed. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy. It is noteworthy that the endogenous ligands of CB1/CB2 and GPR55 are closely related (Fig. 1, Fig. 6). Further studies on the pharmacology and actions/metabolism of endogenous ligands (Fig. 1, Fig. 6) are needed for the clinical usage of related compounds. Our studies are important because the evidence we obtained connected research for lysophospholipid mediators and cannabinoids.
    Acknowledgements We thank Mr. Makoto Ito for preparing the endothelin receptor antagonist tree for GPCR and phospholipases. This study was supported in part by a Grant-in-Aid for Scientific Research (21590075, 24590095) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan.
    GPR55, a recently deorphanized, rhodopsin-like (class A) G protein-coupled receptor (GPCR), is a receptor for -α-lysophosphatidylinositol (LPI, ) which serves as the endogenous agonist (GenBank entry NM 005683). Initial studies noted that a variety of CB1 and CB2 ligands bind to GPR55, and more recent studies have focused on physiological roles for GPR55 in inflammatory pain, neuropathic pain, bone development, and the potential for activation of GPR55 being pro-carcinogenic., , , , Despite the important potential biological functions of GPR55, the research is limited by the lack of both potent and selective agonists and antagonists., Based on a high-throughput, high-content screen of approximately 300,000 compounds from the Molecular Libraries Probe Production Centers Network initiative, a few molecular scaffolds were identified that had relatively good selectivity and potency as antagonists at GPR55. These structures were then docked into the inactive state model of GPR55 to visualise the key features of the antagonists. Of the compounds that exhibited selective and moderate activity as antagonists at GPR55, three different structural families were identified as illustrated by ML191, ML192, and ML193 (). The docking of the structures in into the inactive state model of GPR55 indicated a few important interactions as we previously reported. Briefly, the primary interaction was hydrogen bonding between the lysine at position 2.60(80) and the oxadiazolone carbonyl in ML191, the amide carbonyl in ML192, or an oxygen of the sulfonamide in ML193. The hypothesised interactions with K2.60(80) positioned the bottom aryl rings of all three structures, as represented in , to maintain the toggle switch interaction between M3.36(105) and F6.48(239). The remaining interactions of the ligands presented in and GPR55 are primarily aromatic stacking with various residues. Specifically for ML191, the toluene ring attached to the cyclopropane stacks with F169 and the phenyl group attached to the oxadiazolone stacks with F6.55(246) and F3.33(102; ). In addition to these interactions, moderate beneficial van der Waals interactions were identified between the oxadiazolone and both M7.39(274) and Y3.32(101). Since the interactions between ML191 and GPR55 centred on the three aromatic rings of ML191, compounds were desired that modified the electronics and sterics of these areas. Hence, the ML191 synthetic studies reported herein were undertaken to explore the SAR of this oxadiazolone class of compounds. ML191 was also chosen as the lead antagonist since there are very few structurally related compounds that could be purchased and screened compared to the available compounds for ML192 and ML193.