Anticonvulsant effects of new coumarin-2,3-dimethylbutadiene Diels-Alder cycloadducts in the pentylenetetrazole-induced clonic seizures in mice

• Published in: Bioorganic & medicinal chemistry letters 2025-04, Vol.118, p.130089, Article 130089
• Main Authors: Santiago-Quintana, José Martín, Soriano-Ursúa, Marvin A., Trujillo-Ferrara, José G., Correa-Basurto, José, Espinosa-Raya, Judith, López-Castro, Yliana, García-Baez, Efrén V., Padilla-Martínez, Itzia I.
• Format: Article
• Language: English
• Subjects: Cannabinoid receptors; Diels-Alder cycloadducts; Pentylenetetrazole; Seizures; Synthetic cannabinoids
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2024.130089

[Display omitted] •Experimental pKi of cycloadducts are higher than phytocannabinoids in CB receptors.•Coumarin 3-substituted core act as good dienophile in solvent free conditions.•Crystallographic analysis approximate the relative stability of new drugs.•Motor activity is increased after the administration of cycloadducts in mice.•Clonic seizures induced by PTZ in mice are delayed by the novel compounds. Cannabis sativa oil has emerged as an alternative for the treatment of seizures while failing of conventional treatments. Since some coumarins are recently reported active as anticonvulsants, then, it is necessary to expand the catalog of cannabinoid-analogous compounds based on coumarins. Herein, we report the solvent-free synthesis of coumarin Diels-Alder cycloadducts structurally related to cannabinoids, their chemical characterization, X-ray structures, biosimulation profiles, and in vivo assessment. Theoretical evaluations exhibit their high affinity for the cannabinoid receptors (CB1 and CB2), making interactions with the amino acid residues from the orthosteric site, with free energy of binding values from −10.4 to −10.6 kcal/mol for CB1, and −10.8 to −11.3 kcal/mol for CB2. Additionally, pharmacokinetic properties (ADMET) were computed. Lorke’s method was used to find the mean lethal dose (LD50) of the target compounds exhibiting acute dead doses upper than 1000 mg kg−1. An open field test was performed to evaluate motor activity after the treatment with the target compounds, showing no motor disruption after their administration; and their anticonvulsant activities were evaluated on a pentylenetetrazole-induced clonic seizure model in mice compared to the synthetic cannabinoid WIN55. The behavioral results support the reported Diels-Alder cycloadducts act in the central nervous system, as they have anti-seizure effect in a similar way to WIN55. Results suggest their mechanism of action may involve both the GABAergic and endocannabinoid pathways.