Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

  1. Gentaroh Suzuki,
  2. Toshifumi Kimura,
  3. Akio Satow,
  4. Naoki Kaneko,
  5. Junko Fukuda,
  6. Hirohiko Hikichi,
  7. Naoko Sakai,
  8. Shunsuke Maehara,
  9. Hiroko Kawagoe-Takaki,
  10. Mikiko Hata,
  11. Tomoko Azuma,
  12. Satoru Ito,
  13. Hiroshi Kawamoto and
  14. Hisashi Ohta
  1. Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan
  1. Address correspondence to:
    Gentaroh Suzuki, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. E-mail: gentaroh_suzuki{at}merck.com

Abstract

A highly potent and selective metabotropic glutamate receptor (mGluR) 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), is described. FTIDC inhibits, with equal potency, l-glutamate-induced intracellular Ca2+ mobilization in Chinese hamster ovary cells expressing human, rat, or mouse mGluR1a. The IC50 value of FTIDC is 5.8 nM for human mGluR1a and 6200 nM for human mGluR5. The maximal response in agonist concentration-response curves was reduced in the presence of higher concentrations of FTIDC, suggesting the inhibition in a noncompetitive manner. FTIDC at 10 μM showed no agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8. FTIDC did not displace [3H]l-quisqualate binding to human mGluR1a, indicating FTIDC is an allosteric antagonist. Studies using chimeric and mutant receptors of mGluR1 showed that transmembrane (TM) domains 4 to 7, especially Phe801 in TM6 and Thr815 in TM7, play pivotal roles in the antagonism of FTIDC. FTIDC inhibited the constitutive activity of mGluR1a, suggesting that FTIDC acts as an inverse agonist of mGluR1a. Intraperitoneally administered FTIDC inhibited face-washing behavior elicited by a group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine in mice at doses that did not produce motor impairment. Oral administration of FTIDC also inhibited the face-washing behavior. FTIDC is a highly potent and selective allosteric mGluR1 antagonist and a compound having oral activity without species differences in its antagonistic activity on recombinant human, mouse, and rat mGluR1. FTIDC could therefore be a valuable tool for elucidating the functions of mGluR1 not only in rodents but also in humans.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.116574.

  • ABBREVIATIONS: mGluR, metabotropic glutamate receptor; TM, transmembrane; CNS, central nervous system; BAY36-7620, [(3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on]; EM-TBPC, 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone; LY456236, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine, HCl; LY456066, (2-[4-(indan-2-ylamino)-5,6,7,8-tetrahydro-quinazolin-2-ylsulfanyl]-ethanol, HCl; YM-298198, 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide; A-841720, 9-dimethylamino-3-(N-hexamethyleneiminyl)-3H-5-thia-1,3,6-triazafluoren-4-one; compound 1, tert-butyl-4-(1-phenyl-1H-1,2,3-triazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate; compound 2, tert-butyl-4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate; FTIDC, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide; LY367385, (+)-2-methyl-4-carboxyphenylglycine; LY341495, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; l-AP4, l-(+)-2-amino-4-phosphonobutyric acid; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine; R21427, 1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone; GTPγS, guanosine 5′-O-(3-thio)triphosphate; dhfr, dihydrofolate reductase; CHO, Chinese hamster ovary; DMEM, Dulbecco's modified Eagle's medium; PCR, polymerase chain reaction; rGLAST, rat glutamate/aspartate transporter; RT-PCR, reverse transcription-polymerase chain reaction; PBS, phosphate-buffered saline; MOPS, 3-(N-morpholino)propanesulfonic acid; HEK, human embryonic kidney; FLIPR, fluorometric imaging plate reader; IP, inositol phosphates; NMDA, N-methyl-d-aspartate; SIB-1893, 2-methyl-6-(2-phenylethenyl)pyridine; MPEP, 2-methyl-6-(phenylethynyl)pyridine; RFU, relative fluorescence units; DMSO, dimethyl sulfoxide.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received November 19, 2006.
    • Accepted March 12, 2007.
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  1. Published online before print March 14, 2007, doi: 10.1124/jpet.106.116574 JPET June 2007 vol. 321 no. 3 1144-1153
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