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Discovery of Novel 1,2,4‐Triazol‐5‐Ones as Tumor Necrosis Factor‐Alpha Inhibitors for the Treatment of Neuropathic Pain
Author(s) -
Sharma Monika,
Garigipati Sowmya,
Kundu Binita,
Vanamala Deekshith,
Semwal Arvind,
Sriram Dharmarajan,
Yogeeswari Perumal
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12049
Subject(s) - neuropathic pain , allodynia , hyperalgesia , neurotoxicity , pharmacology , medicine , analgesic , sciatic nerve , chronic pain , anesthesia , chemistry , nociception , toxicity , receptor , psychiatry
In this work, synthetic integration of substituted semicarbazides and various aliphatic, aryl and heteroaryl acids into 1,2,4‐triazol‐5‐ones was accomplished. Following the assessment of neurotoxicity and peripheral analgesic activity, the compounds were evaluated in two peripheral models of neuropathic pain, the chronic constriction injury and partial sciatic nerve ligation to assess their antihyperalgesic and antiallodynic potential. ED 50 studies undertaken for selected compounds exhibiting promising efficacies ( 1c , 3c and 4a ) revealed values ranging from 13.21 to 39.85 mg/kg in four behavioral assays of hyperalgesia and allodynia (spontaneous pain, tactile allodynia, cold allodynia, and mechanical hyperalgesia). Mechanistic studies revealed that the compounds suppressed the inflammatory component of the neuropathic pain inhibiting tumor necrosis factor‐alpha and preventing oxidative and nitrosative stress.