Piperidine Derivatives: Synthesis, Pharmacological Evaluation and Insilico Approach of Novel Potential Analgesics in 4-amino Methyl Piperidine Series

Abstract

Piperidine is an essential moiety of morphine, responsible for the analgesic activity. Among number of other analgesic targets, µ-opioid receptor is still the most focused and therapeutically important in the management of pain. In this study, a series of novel derivatives of 4 amino methyl piperidine were synthesized and explored for analgesic potential against mu opioid receptor. Their structures were elucidated by FT-IR, 1H NMR, and LC-MS followed by in vivo analgesic evaluation by tail-flick method and writhing test. Among all derivatives, HN58 showed excellent analgesic activity (100% inhibition) in writhing test. Furthermore, reduction of HN58 analgesic effect by naloxone suggests its involvement with µ-OR. Molecular docking approach was also utilized to compare the analgesic potential of synthesized derivatives in order to find potent µ-OR inhibitors, we designed five piperidine derivatives with analgesic activity. We have elucidated the binding affinities and binding modes of these piperidine derivatives including standard molecules Morphine, Fentanyl Pethidine and DAMGO revealed a well-known µ-O inhibitor (having binding affinity ranges from −8.13 to −13.37 kcal/mol). All novel derivatives exhibited the remarkable binding score and encapsulated in the binding pocket of transmembraneous helices engaged by the residues Q124, W133, I144, D147, Y148, M151, V236, I296, H297, W318, I322, and Y236. All derivatives revealed excellent binding scores and interaction mechanism as compared to morphine, pethidine, and fentanyl respectively.