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.
Footnotes
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This work was supported by National Institutes of Health grants NS053536 (to C.M.N.), NS051342, NS031373, MH074953, and NS048334 (to P.J.C.), the Dystonia Research Foundation (to Z.X.), the Alpha Foundation (to P.J.C.), and the Michael J. Fox Foundation (to P.J.C.).
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C.M.N. and K.A.J. contributed equally to this work.
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ABBREVIATIONS: mGluR, metabotropic glutamate receptor; GPCR, G protein-coupled receptor; HTS, high-throughput screening; GIRK, G-protein-regulated inwardly rectifying potassium channel; HEK, human embryonic kidney; DMSO, dimethyl sulfoxide; PHCCC, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide; MPEP, 2-methyl-6-(phenylethynyl)pyridine hydrochloride; LY341495, (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; Ro25-6981, (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol; NMDA, N-methyl-d-asparate; VU0003423, 2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid; VU0155040, (±)-trans-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid; VU0155041, (±)-cis-2-(3,5-dicholorphenylcarbamoyl)-cyclohexanecarboxylic acid; l-AP4, l-(+)-amino-4-phosphonobutyric acid; TVC, third ventricle cannulated; PD, Parkinson's disease; PAM, positive allosteric modulator; icv, intracerebroventricular; CHO, Chinese hamster ovary; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; HEK, human embryonic kidney; FDSS, Functional Drug Screening System; BHK, baby hamster kidney; GTPγS, guanosine 5′-O-(3-thio)triphosphate; ACSF, artificial cerebrospinal fluid; NMDAR, N-methyl-d-aspartate receptor; GPe, globus pallidus external segment; SNr, substantia nigra pars reticulata; QX-314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide; SIB-1893, 2-methyl-6-(2-phenylethenyl)pyridine.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received June 6, 2008.
- Accepted July 29, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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