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A Close Structural Analog of 2-Methyl-6-(phenylethynyl)-pyridine Acts as a Neutral Allosteric Site Ligand on Metabotropic Glutamate Receptor Subtype 5 and Blocks the Effects of Multiple Allosteric Modulators

Department of Pharmacology and Program in Translational Neuropharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (A.L.R., Y.N., N.K.S., P.J.C.); and Institute for Neurodegenerative Disorders, New Haven, Connecticut (D.A., G.D.T.)

The metabotropic glutamate receptor subtype 5 (mGlu5) activates calcium mobilization via binding of glutamate, the major excitatory neurotransmitter in the central nervous system. Allosteric modulation of the receptor has recently emerged as a promising alternative method of regulation to traditional regulation through orthosteric ligands. We now report three novel compounds that bind to the allosteric 2-methyl-6-(phenylethynyl)-pyridine (MPEP) site on mGlu5 but have only partial inhibition or no functional effects on the mGlu5 response. Two of these compounds, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) and 2-(2-(5-bromopyridin-3-yl)ethynyl)-5-methylpyridine (Br-5MPEPy), act as partial antagonists of mGlu5 in that they only partially inhibit the response of this receptor to glutamate. The third compound, 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), acts as a neutral allosteric site ligand that binds to the MPEP site and has no effects alone. However, 5MPEP blocks the effects of both the allosteric antagonist MPEP and potentiators 3,3'-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). This compound also blocks depolarization effects of both MPEP and CDPPB in neurons in the subthalamic nucleus. These novel compounds provide valuable new insight into the pharmacology of allosteric sites on G protein-coupled receptors and provide valuable new tools for determining the effects of allosteric site ligands in native systems.

Received for publication June 29, 2005.

Accepted for publication September 9, 2005.

Address correspondence to: Dr. P. Jeffrey Conn, Department of Pharmacology, Vanderbilt University Medical Center, 23rd Ave. South at Pierce, 417-D Preston Research Bldg., Nashville, TN 37232-6600. E-mail: jeff.conn{at}vanderbilt.edu

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