ABSTRACT
Seven new ajmaline type alkaloids, alstiphyllanines I-O (1-7) were isolated from the leaves of Alstonia macrophylla together with six related alkaloids (8-13). Structures and stereochemistry of 1-7 were fully elucidated and characterized by 2D NMR analysis. A series of alstiphyllanines I-O (1-7) as well as the known ajmaline type alkaloids (8-13) showed that they relaxed phenylephrine (PE)-induced contractions against rat aortic ring. Among them, vincamedine (10) showed potent vasorelaxant activity, which may be mediated through inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs) as well as partially mediated the NO release from endothelial cells. The presence of substituents at both N-1 and C-17 may be important to show vasorelaxation activity.
Subject(s)
Ajmaline/analogs & derivatives , Ajmaline/chemistry , Alstonia/chemistry , Secologanin Tryptamine Alkaloids/chemistry , Secologanin Tryptamine Alkaloids/pharmacology , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacology , Ajmaline/pharmacology , Animals , Aorta/drug effects , Aorta/metabolism , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Endothelial Cells/drug effects , Endothelial Cells/metabolism , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Molecular Structure , Nitric Oxide/metabolism , Phenylephrine/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Vasodilation/drug effectsABSTRACT
Five bisbenzyl isoquinolines (1-5), three benzyl isoquinolines (6-8), four isoquinoline alkaloids (9-12), and two unclassified compounds (13 and 14) from Popowia perakensis and Phaeanthus crassipetalus were evaluated for their vasorelaxant effect on rat aortic arteries. In aortic rings pre-contracted with phenylephrine (PE, 0.3 µM), some of the bisbenzyl isoquinoline alkaloids, benzyl isoquinoline alkaloids, and isoquinoline alkaloids showed clearly vasorelaxant effects at 30 µM. The action of (-)-limacine (4) was deduced to be mediated through the increased release of NO from endothelial cells, and that of pecrassipine A (7) and backebergine (12) partly mediated by NO release. Further, the action of pecrassipine A (7) and backebergine (12) may be attributed to their inhibition of the voltage-dependent Ca(2+) channel and receptor-operated Ca(2+) channel.