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to Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery. | LitMetric
Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined with concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu) positive allosteric modulators (PAMs) and their relevance to concentration-response relationships. These studies identified a significant relationship between PAM cooperativity (αβ), as well as the maximal response obtained from a simple PAM concentration-response experiment, with efficacy for reversal of amphetamine-induced hyperlocomotion. This correlation did not exist with PAM potency or affinity. Data across PAMs were then converged to calculate an concentration of glutamate putatively relevant to the mGlu PAM mechanism of action. This work demonstrates the ability to merge pharmacology profiles with relevant behavioral outcomes and also provides a novel method to estimate neurotransmitter concentrations .
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