Host: The Japanese Pharmacological Society
Name : The 96th Annual Meeting of the Japanese Pharmacological Society
Number : 96
Location : [in Japanese]
Date : November 30, 2022 - December 03, 2022
Glutamate neurotransmission is mediated via ionotropic and metabotropic glutamatereceptors (mGlu). By acting at alternate non-conserved sites at the mGlu5subtype, allosteric modulators offer promise to treat a range ofneurodegenerative and psychiatric disorders. Allosteric modulators fine-tunereceptor activity with spatio-temporal control, greater subtype selectivity andcan bias mGlu5 activity to preference different cellular responses. Our centralhypothesis is previously unappreciated biased activation and modulation of mGlu5underpins translational failures of diverse allosteric modulators.
To build a more complete molecular fingerprint we assess multiple measures ofmGlu5 activity using a combination of recombinant cells expressing human or ratmGlu5 as well as primary brain cell cultures. Rigorous analytical methods allowquantification of allosteric modulator cooperativity and affinity from kineticbinding assays, as well as second messenger and compartmentalised kinasebiosensor assays. We found structurally diverse mGlu5 allosteric modulators havedistinct kinetic profiles and differentially influence mGlu5 activity in aspatio/temporal fashion. Probe dependence was evident for modulating glutamateversus quisqualate. This has implications for translating profiles in primarybrain cell cultures to in vivo effects.
By linking molecular pharmacological properties to known preclinical and clinicaleffects, we seek to provide an enriched understanding of the drivers of efficacyas well as failures. We imagine these molecular fingerprints of mGlu5 allostericmodulators can be employed to triage undesirable compounds and streamline futuredrug discovery efforts.
