1. Novel pyrrole based CB2 agonists: New insights on CB2 receptor role in regulating neurotransmitters' tone.
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Di Micco, Simone, Ciaglia, Tania, Salviati, Emanuela, Michela, Perrone, Kostrzewa, Magdalena, Musella, Simona, Schiano Moriello, Aniello, Di Sarno, Veronica, Smaldone, Gerardina, Di Matteo, Francesca, Capolupo, Ilaria, Infantino, Rosmara, Bifulco, Giuseppe, Pepe, Giacomo, Sommella, Eduardo M., Kumar, Poulami, Basilicata, Manuela Giovanna, Allarà, Marco, Sánchez-Fernández, Nuria, and Aso, Ester more...
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SCOPOLAMINE , *TROPANES , *NEUROTRANSMITTERS , *SEROTONIN , *PYRROLES , *LEAD compounds , *MENTAL illness , *NEURODEGENERATION - 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. [Display omitted] • New chemotypes were designed in silico as CB2 receptor agonists. • In vitro assays revealed compound 70 as potent CB2 agonists. • In vivo scopolamine-induced amnesia model highlighted the efficacy of compound 70. • Tetrad assay confirmed compound 70 CB2-mediated central effects. • MALDI-imaging shed light on the influence of CB2 activation over neurotransmitters. [ABSTRACT FROM AUTHOR] more...
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- 2024
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