Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype

Alice L Rodriguez; Richard Williams; Ya Zhou; Stacey R Lindsley; Uyen Le; Mark D Grier; C David Weaver; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2009.04.110

Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3209-13. doi: 10.1016/j.bmcl.2009.04.110. Epub 2009 May 3.

Authors

Alice L Rodriguez¹, Richard Williams, Ya Zhou, Stacey R Lindsley, Uyen Le, Mark D Grier, C David Weaver, P Jeffrey Conn, Craig W Lindsley

Affiliation

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Abstract

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation
Drug Discovery
Heterocyclic Compounds, 3-Ring / chemistry*
Heterocyclic Compounds, 3-Ring / pharmacology
Humans
Inhibitory Concentration 50
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Structure-Activity Relationship

Substances

GRM5 protein, human
Heterocyclic Compounds, 3-Ring
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate

Abstract

Publication types

MeSH terms

Substances

Grants and funding