title: Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4.
abstract: 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.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA. colleen.niswender@vanderbilt.edu
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Kari A
authors.initials: KA
authors.lastname: Johnson
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Luo
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Joy E
authors.initials: JE
authors.lastname: Marlo
authors.forename: Tomas
authors.initials: T
authors.lastname: de Paulis
authors.forename: Analisa D
authors.initials: AD
authors.lastname: Thompson
authors.forename: Emily L
authors.initials: EL
authors.lastname: Days
authors.forename: Tasha
authors.initials: T
authors.lastname: Nalywajko
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Austin
authors.forename: Michael Baxter
authors.initials: MB
authors.lastname: Williams
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ayala
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016466:CHO Cells; D003342:Corpus Striatum / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000978:Antiparkinson Agents; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4