Skip to Content
Merck
  • Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.

Nature (2015-11-10)
Xi-Ping Huang, Joel Karpiak, Wesley K Kroeze, Hu Zhu, Xin Chen, Sheryl S Moy, Kara A Saddoris, Viktoriya D Nikolova, Martilias S Farrell, Sheng Wang, Thomas J Mangano, Deepak A Deshpande, Alice Jiang, Raymond B Penn, Jian Jin, Beverly H Koller, Terry Kenakin, Brian K Shoichet, Bryan L Roth
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium hydroxide, BioUltra, for luminescence, ≥98.0% (T), pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
3-Ethyl-2,4-pentanedione, mixture of tautomers, 98%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide solution, BioUltra, for molecular biology, 10 M in H2O
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
3-Amino-1,2,4-triazole, ≥95% (TLC)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Anti-HA antibody, Mouse monoclonal, clone HA-7, purified from hybridoma cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, reagent grade, 97%, flakes
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide solution, 50% in H2O
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, ACS reagent, ≥97.0%, pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, reagent grade, ≥98%, pellets (anhydrous)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide solution, 1.0 N, BioReagent, suitable for cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, ultra dry, powder or crystals, 99.99% trace metals basis
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, BioXtra, ≥98% (acidimetric), pellets (anhydrous)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, anhydrous, free-flowing, Redi-Dri, reagent grade, ≥98%, pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, puriss. p.a., ACS reagent, reag. Ph. Eur., K ≤0.02%, ≥98%, pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, beads, 16-60 mesh, reagent grade, 97%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, reagent grade, 97%, powder
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide solution, purum, ≥32%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, puriss., meets analytical specification of Ph. Eur., BP, NF, E524, 98-100.5%, pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide solution, 5.0 M
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, puriss. p.a., ACS reagent, K ≤0.02%, ≥98.0% (T), pellets
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide, pellets, semiconductor grade, 99.99% trace metals basis
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Uracil, ≥99.0%
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Uracil, BioReagent, suitable for cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
4H-1,2,4-Triazol-3-amine, AldrichCPR
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Sodium hydroxide-16O solution, 20 wt. % in H216O, 99.9 atom % 16O
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Ogerin, ≥98% (HPLC)
SKU
Pack Size
Availability
Price
Quantity