Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Richard Williams; Jason T Manka; Alice L Rodriguez; Paige N Vinson; Colleen M Niswender; C David Weaver; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer

doi:10.1016/j.bmcl.2011.01.044

Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1350-3. doi: 10.1016/j.bmcl.2011.01.044. Epub 2011 Jan 18.

Authors

Richard Williams¹, Jason T Manka, Alice L Rodriguez, Paige N Vinson, Colleen M Niswender, C David Weaver, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Shaun R Stauffer

Affiliation

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

Abstract

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.

Published by Elsevier Ltd.

MeSH terms

Allosteric Regulation
Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology
Bridged Bicyclo Compounds / chemical synthesis*
Bridged Bicyclo Compounds / chemistry*
Bridged Bicyclo Compounds / pharmacology
Inhibitory Concentration 50
Lactams / chemical synthesis*
Lactams / chemistry*
Lactams / pharmacology
Molecular Structure
Rats
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship

Substances

Antipsychotic Agents
Bridged Bicyclo Compounds
Lactams
Receptors, Metabotropic Glutamate

Grants and funding

R01 NS031373/NS/NINDS NIH HHS/United States