Abstract
Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.
Keywords:
Metabotropic glutamate receptor; Neuropathic pain; Thiophene derivatives; mGluR1 antagonist.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Publication types
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Evaluation Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Analgesics / administration & dosage
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Analgesics / chemistry*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology*
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Animals
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Cells, Cultured
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Disease Models, Animal*
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Drug Discovery*
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HEK293 Cells
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Humans
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Male
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Microsomes, Liver / drug effects
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Neuralgia / drug therapy*
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Nitriles / administration & dosage
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Nitriles / chemistry*
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Nitriles / pharmacokinetics
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Nitriles / pharmacology*
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Pyridines / administration & dosage
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / metabolism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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2-(benzylamino)-6-(3-methyl-1H-pyrazole-5-carbonyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile
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2-(benzylamino)-6-(4-fluorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile
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Analgesics
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Nitriles
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Pyridines
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor type 1
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pyridine