Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 as Tool Compounds to Study Signaling Bias

Positive allosteric modulation of metabotropic glutamate subtype 5 (mGlu5) receptor has emerged as a potential new therapeutic strategy for the treatment schizophrenia and cognitive impairments. However, positive modulator (PAM) agonist activity been associated with adverse side effects, neurotoxicity also observed pure PAMs. The structural pharmacological basis versus mGlu5 PAM in vivo effects remains unknown. Thus, gaining insights into signaling fingerprints, well binding kinetics structurally diverse PAMs, may help rational design compounds desired properties. We assessed profiles N-methyl-5-(phenylethynyl)pyrimidin-2-amine (MPPA), 3-cyano-N-(2,5-diphenylpyrazol-3-yl)benzamide (CDPPB), 1-[4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl]-2-(4-pyridylmethoxy)ethenone [compound 2c, close analog 1-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone] human embryonic kidney 293A cells stably expressing using Ca2+ mobilization, inositol monophosphate (IP1) accumulation, extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, internalization assays. Of three ligands, only CDPPB had intrinsic efficacy, it longest residence time highest affinity. MPPA was biased PAM, showing higher cooperativity orthosteric agonists ERK1/2 phosphorylation mobilization over IP1 accumulation internalization. In primary cortical neurons, all PAMs showed stronger (S)-3,5-dihydroxyphenylglycine (DHPG) accumulation. Our characterization provides further molecular presents first assessment PAM-mediated SIGNIFICANCE STATEMENT Enhancing is promising to treat symptoms schizophrenia. It increasingly evident that modulators (PAMs) are not equal preclinical models; there need better understand properties This study reports detailed functional on