Ullah Qarib, Ali Zarshad, Rashid Umer, Ali Gowhar, Ahmad Nisar, Khan Rasool, Ullah Sami, Ayaz Muhammad, Murthy H C Ananda
Department of Chemistry, Hazara University, Mansehra 21310, Pakistan.
Department of Chemistry, COMSATS University Islamabad-Abbottabad Campus, 22060 Abbottabad, Pakistan.
ACS Omega. 2023 Jun 12;8(25):22809-22819. doi: 10.1021/acsomega.3c01717. eCollection 2023 Jun 27.
Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. The current work aims to evaluate a novel indazolone derivative against and targets of pain, neuropathy, and inflammation. An indazolone derivative (ID) was synthesized and characterized using advanced spectroscopic techniques. Well-established animal models of abdominal constriction, hot plate, tail immersion, carrageenan paw edema, and Brewer's yeast-induced pyrexia were employed for evaluating the potential of the ID at different doses (20-60 mg kg). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) and pentylenetetrazole (PTZ), were employed to assess the potential role of GABAergic and opioidergic processes. The antineuropathic potential of the drug was evaluated using a vincristine-induced neuropathic pain model. studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABA, and opioid receptors. This study revealed that the selected ID (doses of 20-60 mg kg) efficiently hampered chemically and thermally induced nociceptive responses, producing significant anti-inflammatory and antipyretic effects. These effects produced by the ID were dose-dependent (i.e., 20-60 mg kg and range of 0.001-0.01) and significant in comparison to standards ( < 0.001). Antagonistic studies with NLX (1.0 mg kg) and PTZ (15.0 mg kg) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABA, and opioid receptors. According to the results of the current investigation, the ID may serve in the future as a therapeutic agent for the treatment of pyrexia, chemotherapy-induced neuropathic pain, and nociceptive inflammatory pain.
吲唑酮具有有趣的药理活性。寻找含吲唑和吲唑酮的核作为药物是药物化学的一个重要研究领域。当前的工作旨在评估一种新型吲唑酮衍生物对疼痛、神经病变和炎症的靶点的作用。合成了一种吲唑酮衍生物（ID），并使用先进的光谱技术对其进行了表征。采用成熟的腹部收缩、热板、尾浸、角叉菜胶足肿胀和布鲁氏酵母诱导发热的动物模型，以评估不同剂量（20 - 60毫克/千克）的ID的潜力。使用非选择性GABA拮抗剂、阿片类拮抗剂纳洛酮（NLX）和戊四氮（PTZ）来评估GABA能和阿片能过程的潜在作用。使用长春新碱诱导的神经病理性疼痛模型评估该药物的抗神经病变潜力。进行了研究以评估ID与疼痛靶点如环氧化酶（COX - I/II）、GABA和阿片受体之间的任何可能相互作用。这项研究表明，所选的ID（20 - 60毫克/千克剂量）有效地阻碍了化学和热诱导的伤害性反应，产生了显著的抗炎和解热作用。ID产生的这些作用是剂量依赖性的（即20 - 60毫克/千克，范围为0.001 - 0.01），与标准相比具有显著性（P < 0.001）。与NLX（1.0毫克/千克）和PTZ（15.0毫克/千克）的拮抗研究表明，涉及的是阿片能机制而非GABA能机制。ID还显示出有前景的抗静态异常性疼痛作用。研究揭示了ID与环氧化酶（COX - I/II）、GABA和阿片受体之间的优先结合相互作用。根据当前研究的结果，ID未来可能作为一种治疗药物用于治疗发热、化疗诱导的神经病理性疼痛和伤害性炎性疼痛。
