Novel pyrrole based CB2 agonists: New insights on CB2 receptor role in regulating neurotransmitters' tone

  • Eur J Med Chem. 2024 Mar 11:269:116298. doi: 10.1016/j.ejmech.2024.116298.
Simone Di Micco  1 ,  Tania Ciaglia  2 ,  Emanuela Salviati  2 ,  Perrone Michela  3 ,  Magdalena Kostrzewa  4 ,  Simona Musella  2 ,  Aniello Schiano Moriello  4 ,  Veronica Di Sarno  2 ,  Gerardina Smaldone  2 ,  Francesca Di Matteo  2 ,  Ilaria Capolupo  2 ,  Rosmara Infantino  3 ,  Giuseppe Bifulco  2 ,  Giacomo Pepe  2 ,  Eduardo M Sommella  2 ,  Poulami Kumar  4 ,  Manuela Giovanna Basilicata  2 ,  Marco Allarà  4 ,  Nuria Sánchez-Fernández  5 ,  Ester Aso  5 ,  Isabel M Gomez-Monterrey  6 ,  Pietro Campiglia  2 ,  Carmine Ostacolo  2 ,  Sabatino Maione  3 ,  Alessia Ligresti  7 ,  Alessia Bertamino  8
Affiliations
  • 1. European Biomedical Research Institute (EBRIS), Via S. De Renzi 50, 84125, Salerno, Italy.
  • 2. Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 3. Department of Experimental Medicine, Pharmacology Division, University of Campania "L. Vanvitelli", 80138, Naples, Italy.
  • 4. Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 34, 80078, Pozzuoli, Naples, Italy.
  • 5. Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131, Naples, Italy; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907, L'Hospitalet de Llobregat, Spain.
  • 6. Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, 08907, L'Hospitalet de Llobregat, Spain.
  • 7. Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 34, 80078, Pozzuoli, Naples, Italy; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907, L'Hospitalet de Llobregat, Spain. Electronic address: [email protected].
  • 8. Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy. Electronic address: [email protected].
PMID: 38493727 DOI: 10.1016/j.ejmech.2024.116298
Abstract

The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as Cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational design of pyrrole-based analogues, which led to a potent and pharmacokinetically suitable CB2 full agonist particularly effective in improving cognitive functions in a scopolamine-induced amnesia murine model. Therefore, we extended our study by investigating the interconnection between CB2 activation and neurotransmission in this experimental paradigm. To this purpose, we performed a MALDI imaging analysis on mice brains, observing that the administration of our lead compound was able to revert the effect of scopolamine on different neurotransmitter tones, such as acetylcholine, serotonin, and GABA, shedding light on important networks not fully explored, so far.

Keywords
Cannabinoid 2 receptor agonists; In silico design; In vitro analysis; In vivo characterization; Maldi-imaging assays.
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