Summary of Image-based HTS for Selective Antagonists of GPR55
The orphan G protein coupled receptor, GPR55, has gained notoriety because of its putative identification as a cannabinoid receptor subtype. The significance of this assignment should not be underestimated given the importance of cannabinoids to drug abuse and the potential utility of cannabinoid ligands in treating behavioral disorders leading to conditions such as obesity. The validity of more ..
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1X01 DA026205-01
Assay Provider: Dr. Mary Abood, California Pacific Medical Center Research Institute
The orphan G protein coupled receptor, GPR55, has gained notoriety because of its putative identification as a cannabinoid receptor subtype. The significance of this assignment should not be underestimated given the importance of cannabinoids to drug abuse and the potential utility of cannabinoid ligands in treating behavioral disorders leading to conditions such as obesity. The validity of assigning GPR55 to the cannabinoid family is problematic based upon the discovery that endogenous compounds not related to cannabinoid receptor ligands also bind and signal through GPR55. As a consequence, it is important to identify GPR55-selective ligands that can precisely define GPR55's role in regulating addictive behaviors. Cannabidiol has been reported as a GPR55 antagonist in the literature to GPR55 activation by O1062, but this could not be confirmed our laboratory (Dr. Abood & Dr. Barak). There are no other known small molecule antagonists of GPR55 reported to date, only the CB1 inverse agonist/antagonists SR141716A (3.9 uM) and AM251 (9.6 uM). We have identified 3 potent and selective antagonists for GPR55, that represent 3 different chemical core scaffolds: 1) a quinoline aryl sulfonamide, ML193 (CID1261822) with a 221 nM potency for GPR55 and >145-fold, >27-fold and >145-fold antagonist selectivity against GPR35, CB1 and CB2, respectively and >145-fold agonist selectivity against all of these counter-receptors; 2) a thienopyrimidine, ML192 (CID1434953) with 1080 nM potency for GPR55 and >45-fold antagonist and agonist selectivity against GPR35, CB1 and CB2; and 3) a piperadinyloxadiazolone, ML191 (23612552) with 160 nM potency for GPR55 and >100-fold selectivity against GPR35, CB1 and CB2. All three probes also are active in inhibiting the downstream responses of ERK phosphorylation and PKC beta II translocation.
Please see pertinent AIDs: 2013, 2809, 2814, 2815, 2820, 2822, 2835, 2836, 485277, 485278, 485282, 485283, 485285, 485286, 485287, 488947
Probe molecules are defined as the positives of this assay and assigned a score of 100. Compound SIDs 87225762, 87225747 and 87225750 have been identified as probe molecules.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML193
PubChem Substance ID (SID) for probe 1: 87225762
PubChem Compound ID (CID) for probe 1: 1261822
IC50/EC50 (nM) for probe 1: 221
Target for probe 1: GPR55 Antagonist (gi: 33695107)
Anti-target for probe 1: GPR35, CB1, CB2 agonist and antagonist
Fold selectivity for probe 1: 27 - 145
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK66153/ (ID: 2647734)
Grant number for probe 1: DA026205-01
NCBI Book chapter title for probe 1: Screening for Selective Ligands for GPR55 - Antagonists
Data Table (Concise)