Discovery, Characterization, and Antiparkinsonian Effect of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

被引:166
作者
Niswender, Colleen M. [1 ,3 ]
Johnson, Kari A. [1 ,3 ]
Weaver, C. David [1 ,3 ,4 ]
Jones, Carrie K. [1 ,3 ]
Xiang, Zixiu [1 ,3 ]
Luo, Qingwei [1 ,3 ]
Rodriguez, Alice L. [1 ,3 ]
Marlo, Joy E. [1 ,3 ]
de Paulis, Tomas [1 ]
Thompson, Analisa D. [1 ,3 ]
Days, Emily L. [4 ]
Nalywajko, Tasha [4 ]
Austin, Cheryl A. [4 ]
Williams, Michael Baxter [4 ]
Ayala, Jennifer E. [1 ]
Williams, Richard [1 ,3 ]
Lindsley, Craig W. [1 ,2 ,3 ,4 ]
Conn, P. Jeffrey [1 ,3 ,4 ]
机构
[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1124/mol.108.049551
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:1345 / 1358
页数:14
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