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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)
- Source :
- Journal of Medicinal Chemistry. 56:7976-7996
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
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.
- Subjects :
- Metabotropic glutamate receptor 5
Chemistry
Stereochemistry
Allosteric regulation
Glutamate receptor
Neurotoxicity
Cooperativity
Ligand (biochemistry)
medicine.disease
stomatognathic system
embryonic structures
parasitic diseases
Drug Discovery
medicine
Molecular Medicine
Structure–activity relationship
Metabotropic glutamate receptor 2
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........c24f800d249cef552a69bc691def6ed1