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.