ABSTRACT
Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.
Subject(s)
Analgesics/therapeutic use , Phenylurea Compounds/therapeutic use , TRPV Cation Channels/agonists , Thiazoles/therapeutic use , Analgesics/chemical synthesis , Analgesics/pharmacokinetics , Analgesics/toxicity , Animals , CHO Cells , Capsaicin , Cricetulus , Drug Discovery , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Mice, Inbred ICR , Neuralgia/drug therapy , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/toxicity , Swine , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/toxicityABSTRACT
A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase.