Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study
Epilepsy is a chronic neurological disorder that affects nearly 50 million people worldwide. Experimental evidence suggests that epileptic neurons are linked to the endocannabinoid system and that inhibition of the FAAH enzyme could have neuroprotective effects by increasing the levels of endogenous...
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MDPI AG
2025-01-01
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| author | Karin Jannet Vera-López Jorge Alberto Aguilar-Pineda Rodrigo Martín Moscoso-Palacios Gonzalo Davila-Del-Carpio José Luis Manrique-Murillo Badhin Gómez Minerva González-Melchor Rita Nieto-Montesinos |
| author_facet | Karin Jannet Vera-López Jorge Alberto Aguilar-Pineda Rodrigo Martín Moscoso-Palacios Gonzalo Davila-Del-Carpio José Luis Manrique-Murillo Badhin Gómez Minerva González-Melchor Rita Nieto-Montesinos |
| author_sort | Karin Jannet Vera-López |
| collection | DOAJ |
| description | Epilepsy is a chronic neurological disorder that affects nearly 50 million people worldwide. Experimental evidence suggests that epileptic neurons are linked to the endocannabinoid system and that inhibition of the FAAH enzyme could have neuroprotective effects by increasing the levels of endogenous endocannabinoid anandamide. In this context, the use of macamides as therapeutic agents in neurological diseases has increased in recent years. With a similar structure to anandamide, several theories point to the FAAH–macamide interaction as a possible cause of FAAH enzymatic inhibition. In this work, we used in silico and in vivo techniques to analyze the potential therapeutic effect of three synthetic macamides in the treatment of epilepsy: <i>N</i>-3-methoxybenzyl-oleamide (3-MBO), <i>N</i>-3-methoxybenzyl-linoleamide (3-MBL), and <i>N</i>-3-methoxybenzyl-linolenamide (3-MBN). In the first stage, an in silico analysis was conducted to explore the energetic affinity of these macamides with rFAAH and their potential inhibitory effect. MD simulations, molecular docking, and MM/PBSA calculations were used for these purposes. Based on our results, we selected the two best macamides and performed an in vivo study to analyze their therapeutic effect in male Sprague Dawley rat models. Rats were subjected to an in vivo induction of epileptic status by the intraperitoneal injection of pilocarpine and analyzed according to the Racine scale. In silico results showed an energetic affinity of three macamides and a possible “plugging” effect of the membrane access channel to the active site as a potential cause of FAAH inhibition. On the other hand, the in vivo results showed an anticonvulsant effect of both macamides, with 3-MBL being the most active, resulting in a higher survival probability in the rats. This work represents one of the first studies on the use of macamides for the treatment of epilepsy. |
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| spelling | doaj-art-919747b601174b9fafdfae9d7f9c04892025-01-24T13:43:39ZengMDPI AGMolecules1420-30492025-01-0130233310.3390/molecules30020333Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo StudyKarin Jannet Vera-López0Jorge Alberto Aguilar-Pineda1Rodrigo Martín Moscoso-Palacios2Gonzalo Davila-Del-Carpio3José Luis Manrique-Murillo4Badhin Gómez5Minerva González-Melchor6Rita Nieto-Montesinos7Escuela Profesional de Farmacía y Bioquímica, Universidad Católica de Santa María, Urb. San José s/n, Umacollo, Arequipa 04000, PeruInstituto de Física “Luis Rivera Terrazas”, Benemérita Universidad Autónoma de Puebla, Av. San Claudio, Cd. Universitaria, Apdo. Postal J-48, Puebla 72570, MexicoEscuela Profesional de Farmacía y Bioquímica, Universidad Católica de Santa María, Urb. San José s/n, Umacollo, Arequipa 04000, PeruEscuela Profesional de Farmacía y Bioquímica, Universidad Católica de Santa María, Urb. San José s/n, Umacollo, Arequipa 04000, PeruCentro de Investigación en Ingeniería Molecular—CIIM, Universidad Católica de Santa María, Urb. San José s/n—Umacollo, Arequipa 04000, PeruEscuela Profesional de Farmacía y Bioquímica, Universidad Católica de Santa María, Urb. San José s/n, Umacollo, Arequipa 04000, PeruInstituto de Física “Luis Rivera Terrazas”, Benemérita Universidad Autónoma de Puebla, Av. San Claudio, Cd. Universitaria, Apdo. Postal J-48, Puebla 72570, MexicoEscuela Profesional de Farmacía y Bioquímica, Universidad Católica de Santa María, Urb. San José s/n, Umacollo, Arequipa 04000, PeruEpilepsy is a chronic neurological disorder that affects nearly 50 million people worldwide. Experimental evidence suggests that epileptic neurons are linked to the endocannabinoid system and that inhibition of the FAAH enzyme could have neuroprotective effects by increasing the levels of endogenous endocannabinoid anandamide. In this context, the use of macamides as therapeutic agents in neurological diseases has increased in recent years. With a similar structure to anandamide, several theories point to the FAAH–macamide interaction as a possible cause of FAAH enzymatic inhibition. In this work, we used in silico and in vivo techniques to analyze the potential therapeutic effect of three synthetic macamides in the treatment of epilepsy: <i>N</i>-3-methoxybenzyl-oleamide (3-MBO), <i>N</i>-3-methoxybenzyl-linoleamide (3-MBL), and <i>N</i>-3-methoxybenzyl-linolenamide (3-MBN). In the first stage, an in silico analysis was conducted to explore the energetic affinity of these macamides with rFAAH and their potential inhibitory effect. MD simulations, molecular docking, and MM/PBSA calculations were used for these purposes. Based on our results, we selected the two best macamides and performed an in vivo study to analyze their therapeutic effect in male Sprague Dawley rat models. Rats were subjected to an in vivo induction of epileptic status by the intraperitoneal injection of pilocarpine and analyzed according to the Racine scale. In silico results showed an energetic affinity of three macamides and a possible “plugging” effect of the membrane access channel to the active site as a potential cause of FAAH inhibition. On the other hand, the in vivo results showed an anticonvulsant effect of both macamides, with 3-MBL being the most active, resulting in a higher survival probability in the rats. This work represents one of the first studies on the use of macamides for the treatment of epilepsy.https://www.mdpi.com/1420-3049/30/2/333macamidesepilepsyneuroprotective effectsrFAAHmolecular dynamics |
| spellingShingle | Karin Jannet Vera-López Jorge Alberto Aguilar-Pineda Rodrigo Martín Moscoso-Palacios Gonzalo Davila-Del-Carpio José Luis Manrique-Murillo Badhin Gómez Minerva González-Melchor Rita Nieto-Montesinos Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study Molecules macamides epilepsy neuroprotective effects rFAAH molecular dynamics |
| title | Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study |
| title_full | Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study |
| title_fullStr | Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study |
| title_full_unstemmed | Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study |
| title_short | Anticonvulsant Effects of Synthetic <i>N</i>-(3-Methoxybenzyl)oleamide and <i>N</i>-(3-Methoxybenzyl)linoleamide Macamides: An In Silico and In Vivo Study |
| title_sort | anticonvulsant effects of synthetic i n i 3 methoxybenzyl oleamide and i n i 3 methoxybenzyl linoleamide macamides an in silico and in vivo study |
| topic | macamides epilepsy neuroprotective effects rFAAH molecular dynamics |
| url | https://www.mdpi.com/1420-3049/30/2/333 |
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