Abstract
A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.
MeSH terms
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Administration, Oral
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Analgesics / chemical synthesis
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Analgesics / pharmacology*
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Animals
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Arachidonic Acids / pharmacology
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Calcium / metabolism
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Capsaicin / pharmacology
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Disease Models, Animal
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Dopamine / analogs & derivatives
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Dopamine / pharmacology
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Dose-Response Relationship, Drug
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Hydrogen-Ion Concentration
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Hyperalgesia / drug therapy
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Hyperalgesia / metabolism
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Hyperalgesia / pathology
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Pain Measurement
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Pyridines / administration & dosage*
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Pyridines / chemical synthesis
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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TRPV Cation Channels / antagonists & inhibitors*
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TRPV Cation Channels / metabolism
Substances
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Analgesics
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Arachidonic Acids
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Pyridines
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TRPV Cation Channels
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TRPV1 receptor
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arachidonyl dopamine
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Capsaicin
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Calcium
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Dopamine