vu-0155041 and Parkinson-Disease

vu-0155041 has been researched along with Parkinson-Disease* in 2 studies

Other Studies

2 other study(ies) available for vu-0155041 and Parkinson-Disease

ArticleYear
Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4).
    Bioorganic & medicinal chemistry letters, 2009, Sep-01, Volume: 19, Issue:17

    This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.

    Topics: Allosteric Regulation; Allosteric Site; Anilides; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Parkinson Disease; Rats; Receptors, Metabotropic Glutamate; Structure-Activity Relationship

2009
Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4.
    Molecular pharmacology, 2008, Volume: 74, Issue:5

    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.

    Topics: Allosteric Regulation; Animals; Antiparkinson Agents; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Humans; In Vitro Techniques; Injections, Intraventricular; Male; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Structure-Activity Relationship

2008