Allosteric modulators for G-protein-coupled receptors (GPCRs) offer the potential for enhanced receptor subtype selectivity, reduced desensitization, and improved therapeutic index. Despite these advantages, research focusing on promising family A and C GPCR targets has revealed within some classes of allosteric modulators, unanticipated modulation of efficacy with small structural modifications ('molecular switches'), including generation of ligands with dual allosteric agonism and potentiation (ago-PAM). Ago-PAM ligands of the metabotropic glutamate receptor subtype 5 (mGlu5), for example, induce epileptiform activity and behavioral convulsions in rodents, whereas mGlu5 positive allosteric modulators (PAMs) do not induce these adverse effects. Such mode switching phenomenon has major implications for safety and development of GPCR allosteric modulators since by analogy through drug metabolizing enzymes metabolites may be capable of presenting a range of pharmacological activity (e.g. NAM, PAM, ago-PAM) at the target and/or target family receptors. Examples and strategies for mitigating formation of active allosteric metabolite-ligands will be presented.

Biotransformation of novel allosteric modulators of GPCRs:  Challenges in efficacy modulation, receptor selectivity, and mechanism based adverse events

246th National Meeting (2013)

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