Rigorous Characterization of Allosteric Modulation of the Human Metabotropic Glutamate Receptor 1 Reveals Probe- and Assay-Dependent Pharmacology.

Autor: Muraleetharan A; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Wang Y; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Rowe MC; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Gould A; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Gregory KJ; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Hellyer SD; Drug Discovery Biology (A.M., Y.W., M.C.R., A.G., K.J.G., S.D.H.) and ARC Centre for Cryo-Electron Microscopy of Membrane Proteins (K.J.G.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia shane.hellyer@monash.edu.
Jazyk: angličtina
Zdroj: Molecular pharmacology [Mol Pharmacol] 2023 Jun; Vol. 103 (6), pp. 325-338. Date of Electronic Publication: 2023 Mar 15.
DOI: 10.1124/molpharm.122.000664
Abstrakt: Allosteric modulation of metabotropic glutamate receptor subtype 1 (mGlu 1 ) represents a viable therapeutic target for treating numerous central nervous system disorders. Although multiple chemically distinct mGlu 1 positive (PAMs) and negative (NAMs) allosteric modulators have been identified, drug discovery paradigms have not included rigorous pharmacological analysis. In the present study, we hypothesized that existing mGlu 1 allosteric modulators possess unappreciated probe-dependent or biased pharmacology. Using human embryonic kidney 293 (HEK293A) cells stably expressing human mGlu 1, we screened mGlu 1 PAMs and NAMs from divergent chemical scaffolds for modulation of different mGlu 1 orthosteric agonists in intracellular calcium (iCa 2+ ) mobilization and inositol monophosphate (IP 1 ) accumulation assays. Operational models of agonism and allosterism were used to derive estimates for important pharmacological parameters such as affinity, efficacy, and cooperativity. Modulation of glutamate and quisqualate-mediated iCa 2+ mobilization revealed probe dependence at the level of affinity and cooperativity for both mGlu 1 PAMs and NAMs. We also identified the previously described mGlu 5 selective NAM PF-06462894 as an mGlu 1 NAM with a different pharmacological profile from other NAMs. Differential profiles were also observed when comparing ligand pharmacology between iCa 2+ mobilization and IP 1 accumulation. The PAMs Ro67-4853 and CPPHA displayed apparent negative cooperativity for modulation of quisqualate affinity, and the NAMs CPCCOEt and PF-06462894 had a marked reduction in cooperativity with quisqualate in IP 1 accumulation and upon extended incubation in iCa 2+ mobilization assays. These data highlight the importance of rigorous assessment of mGlu 1 modulator pharmacology to inform future drug discovery programs for mGlu 1 allosteric modulators. SIGNIFICANCE STATEMENT: Metabotropic glutamate receptor subtype 1 (mGlu 1 ) positive and negative allosteric modulators have therapeutic potential in multiple central nervous system disorders. We show that chemically distinct modulators display differential pharmacology with different orthosteric ligands and across divergent signaling pathways at human mGlu 1 . Such complexities in allosteric ligand pharmacology should be considered in future mGlu 1 allosteric drug discovery programs.
(Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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