Your browser doesn't support javascript.
loading
Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.
Cheremnykh, Kirill P; Bryzgalov, Arkadiy O; Baev, Dmitry S; Borisov, Sergey A; Sotnikova, Yulia S; Savelyev, Victor A; Tolstikova, Tatyana G; Sagdullaev, Shamansur S; Shults, Elvira E.
Affiliation
  • Cheremnykh KP; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Bryzgalov AO; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Baev DS; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Borisov SA; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Sotnikova YS; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Savelyev VA; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Tolstikova TG; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
  • Sagdullaev SS; S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, Tashkent 100170, Uzbekistan.
  • Shults EE; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
Molecules ; 28(10)2023 May 22.
Article de En | MEDLINE | ID: mdl-37241973
ABSTRACT
Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.
Sujet(s)
Mots clés

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Benzodiazépines / Aconitine / Analgésiques non narcotiques / Bloqueurs de canaux sodiques voltage-dépendants / Antiarythmiques Limites: Animals Langue: En Journal: Molecules Sujet du journal: BIOLOGIA Année: 2023 Type de document: Article Pays d'affiliation: Russie

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Benzodiazépines / Aconitine / Analgésiques non narcotiques / Bloqueurs de canaux sodiques voltage-dépendants / Antiarythmiques Limites: Animals Langue: En Journal: Molecules Sujet du journal: BIOLOGIA Année: 2023 Type de document: Article Pays d'affiliation: Russie