New allosteric modulators of mGluR5 receptors display therapeutic effects in rodent models of anxiety and drug addiction

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIDA	NEURO/BEHAV/SENSYS-14

* FARE Award Winner

Authors

• T. M. Keck
• M. F. Zou
• P. Zhang
• R. P. Rutledge
• R. Srivastava
• G-H Bi
• H-J Yang
• E. L. Gardner
• Z-X Xi
• A. H. Newman

Abstract

Excess stimulation of metabotropic glutamate receptor subtype 5 (mGluR5), a GPCR highly expressed in mesocorticolimbic brain circuits, is implicated in anxiety and drug abuse. Attenuation of mGluR5 signaling is a promising pharmacotherapeutic approach. To develop new molecular tools and potential lead medications, we designed, synthesized and tested a library of novel mGluR5 ligands targeting an allosteric site on the receptor to inhibit mGluR5 signaling. To improve binding affinity and selectivity over the prototypic mGluR5 negative allosteric modulator (NAM), MPEP, a series of aryl-substituted alkynyl analogues of MPEP was synthesized. Modifications to the MPEP pharmacophore produced six novel compounds with improved binding affinity for mGluR5 and potent inverse agonist characteristics in vitro. Novel high-affinity NAMs MFZ 10-7 and ZP 3-74 produced anxiolytic effects 10-300 times more potently than MPEP in mouse models of anxiety. In rats, MFZ 10-7 and fenobam—a clinically validated mGluR5 NAM—inhibited cocaine self-administration and reinstatement. MFZ 10-7, highly selective for mGluR5 in a broad screen of receptor targets, is a potent NAM that further exemplifies mGluR5 as a viable target for substance use disorder medication development; it was used herein to highlight the potential for fenobam as a clinical candidate for the treatment of cocaine addiction.

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