Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).

Abstract	Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
Authors	Mark Turlington, Meredith J Noetzel, Aspen Chun, Ya Zhou, Rocco D Gogliotti, Elizabeth D Nguyen, Karen J Gregory, Paige N Vinson, Jerri M Rook, Kiran K Gogi, Zixiu Xiang, Thomas M Bridges, J Scott Daniels, Carrie Jones, Colleen M Niswender, Jens Meiler, P Jeffrey Conn, Craig W Lindsley, Shaun R Stauffer
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 20 Pg. 7976-96 (Oct 24 2013) ISSN: 1520-4804 [Electronic] United States
PMID	24050755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide Amides Picolinic Acids Receptor, Metabotropic Glutamate 5 picolinamide Acetylene
Topics	Acetylene (chemical synthesis, chemistry, pharmacology) Allosteric Regulation (drug effects) Amides (chemical synthesis, chemistry, pharmacology) Animals Binding, Competitive Cell Membrane (metabolism) Drug Discovery (methods) Excitatory Postsynaptic Potentials (drug effects) HEK293 Cells Hippocampus (drug effects, physiology) Humans Male Models, Chemical Models, Molecular Molecular Structure Picolinic Acids (chemical synthesis, chemistry, pharmacology) Protein Structure, Tertiary Radioligand Assay Rats Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 (agonists, chemistry, metabolism) Structure-Activity Relationship

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