Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor t...

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Bibliographic Details
Published in:Nature (London) 2015-11, Vol.527 (7579), p.477-483
Main Authors: Huang, Xi-Ping, Karpiak, Joel, Kroeze, Wesley K, Zhu, Hu, Chen, Xin, Moy, Sheryl S, Saddoris, Kara A, Nikolova, Viktoriya D, Farrell, Martilias S, Wang, Sheng, Mangano, Thomas J, Deshpande, Deepak A, Jiang, Alice, Penn, Raymond B, Jin, Jian, Koller, Beverly H, Kenakin, Terry, Shoichet, Brian K, Roth, Bryan L
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Allosteric Site
Animals
Anti-Anxiety Agents - analysis
Anti-Anxiety Agents - chemistry
Anti-Anxiety Agents - metabolism
Anti-Anxiety Agents - pharmacology
Benzyl Alcohols - analysis
Benzyl Alcohols - chemistry
Benzyl Alcohols - metabolism
Benzyl Alcohols - pharmacology
Cell receptors
Conditioning, Classical
Drug Discovery
Fear
Female
Genomes
HEK293 Cells
Humans
Identification and classification
Kinases
Ligands
Ligands (Biochemistry)
Lorazepam - analysis
Lorazepam - chemistry
Lorazepam - metabolism
Lorazepam - pharmacology
Male
Memory - drug effects
Mice
Mice, Knockout
Models, Molecular
Physiological aspects
Physiology
Proteins
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - deficiency
Receptors, G-Protein-Coupled - metabolism
Rodents
Signal Transduction - drug effects
Triazines - analysis
Triazines - chemistry
Triazines - metabolism
Triazines - pharmacology
Yeast
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Summary:At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature15699