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Papers of the Week

Papers: 2 Sep 2023 - 8 Sep 2023

Basic Science

Animal Studies, Neurobiology, Pharmacology/Drug Development

Acute Pain

2023 Aug 30

Eur J Med Chem



Discovery of a novel series of potent carbonic anhydrase inhibitors with selective affinity for μ Opioid receptor for Safer and long-lasting analgesia.


Angeli A, Micheli L, Turnaturi R, Pasquinucci L, Parenti C, Alterio V, Di Fiore A, De Simone G, Monti SM, Carta F, Di Cesare Mannelli L, Ghelardini C, Supuran CT


In this study, we investigated the development of dual-targeted ligands that bind to both μ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8, showing selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. By means of repeated treatment of 3 daily administrations for 17 days, fentanyl (0.1 mg/kg, subcutaneously) led to tolerance development, pain threshold alterations and withdrawal symptoms in CD-1 mice, as well as astrocyte and microglia activation in the dorsal horn of the lumbar spinal cord. In contrast, compound 8 (0.32 mg/kg s.c.) maintained stable during days its analgesic effect at the higher dose tested with fewer withdrawal symptoms, allodynia development and glial cells activation. Our results suggest that targeting both MOR and CA enzymes can lead to the development of new class of potent analgesic agents with fewer side effects and reduced tolerance development. Further studies are needed to explore the potential mechanisms underlying these effects and to further optimize the therapeutic potential of these compounds.