Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

Qarib Ullah; Zarshad Ali; Umer Rashid; Gowhar Ali; Nisar Ahmad; Rasool Khan; Sami Ullah; Muhammad Ayaz; H C Ananda Murthy

doi:10.1021/acsomega.3c01717

Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

ACS Omega. 2023 Jun 12;8(25):22809-22819. doi: 10.1021/acsomega.3c01717. eCollection 2023 Jun 27.

Authors

Qarib Ullah¹, Zarshad Ali¹, Umer Rashid², Gowhar Ali³, Nisar Ahmad⁴, Rasool Khan⁵, Sami Ullah³, Muhammad Ayaz⁶, H C Ananda Murthy^{7

8}

Affiliations

¹ Department of Chemistry, Hazara University, Mansehra 21310, Pakistan.
² Department of Chemistry, COMSATS University Islamabad-Abbottabad Campus, 22060 Abbottabad, Pakistan.
³ Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan.
⁴ School of Pharmacy, Institute of Health Sciences Mardan, Mardan, KPK 23200, Pakistan.
⁵ Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan.
⁶ Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Dir (L), Chakdara, KP 18000, Pakistan.
⁷ Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, P O Box 1888, Adama, Oromia 1888, Ethiopia.
⁸ Department of Prosthodontics, Saveetha Dental College & Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600077, Tamil Nadu, India.

Abstract

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 in vivo and in silico 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^-1). 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. In silico studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABA_A, and opioid receptors. This study revealed that the selected ID (doses of 20-60 mg kg^-1) 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^-1 and p range of 0.001-0.01) and significant in comparison to standards (p < 0.001). Antagonistic studies with NLX (1.0 mg kg^-1) and PTZ (15.0 mg kg^-1) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. In silico studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABA_A, 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.