%0 Journal Article %A Colleen M. Niswender %A Kari A. Johnson %A C. David Weaver %A Carrie K. Jones %A Zixiu Xiang %A Qingwei Luo %A Alice L. Rodriguez %A Joy E. Marlo %A Tomas de Paulis %A Analisa D. Thompson %A Emily L. Days %A Tasha Nalywajko %A Cheryl A. Austin %A Michael Baxter Williams %A Jennifer E. Ayala %A Richard Williams %A Craig W. Lindsley %A P. Jeffrey Conn %T Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4 %D 2008 %R 10.1124/mol.108.049551 %J Molecular Pharmacology %P 1345-1358 %V 74 %N 5 %X Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a positive allosteric modulator (PAM) of mGluR4 that has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency, and poor solubility. Via high-throughput screening, we discovered more than 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, (±)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle, and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased haloperidol-induced catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/74/5/1345.full.pdf