Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]
- Akio Satow,
- Shunsuke Maehara,
- Satoko Ise,
- Hirohiko Hikichi,
- Miyuki Fukushima,
- Gentaroh Suzuki,
- Toshifumi Kimura,
- Takeshi Tanaka,
- Satoru Ito,
- Hiroshi Kawamoto and
- Hisashi Ohta
- Address correspondence to:
Akio Satow, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. E-mail: akio_sato{at}merck.com
Abstract
The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.138107.
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ABBREVIATIONS: CNS, central nervous system; mGluR, metabotropic glutamate receptor; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate; LY379268, (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; iGluR, ionotropic glutamate receptor; NMDA, N-methyl-d-aspartate; MPEP, 2-methyl-6-(phenylethynyl)pyridine; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone; BAY 36-7620, (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-one; YM-230888, N-cycloheptyl-6-({[(2R)-tetrahydrofuran-2-ylmethyl]amino}methyl)thieno[2,3-d]pyrimidin-4-amine; EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)(4-methoxy-cyclohexyl)methanone methanesulfonate; FTIDC, 4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide; DHPG, 3,5-dihydroxyphenylglycine; MAP, methamphetamine; SIH, stress-induced hyperthermia; PPI, prepulse inhibition; CPCCOEt, 7-(hydroxyimino)cyclopropan[b]chromen-1a-carboxylic acid ethyl ester; MK-801, (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; USV, ultrasonic vocalization.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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- Received February 18, 2008.
- Accepted May 16, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
