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- Title
Structure--activity relationship on (±)-nantenine derivatives in antiserotonergic activities in rat aorta.
- Authors
Indra, Bachtiar; Matsunaga, Kimihiro; Hoshino, Osamu; Suzuki, Masaji; Ogasawara, Hiromichi; Ishiguro, Masaji; Ohizumi, Yasushi
- Abstract
A series of nine (±)-nantenine derivatives were synthesized and assayed for their pharmacological activities by using tension in aorta and binding experiments in rat brain membrane. Replacing a methyl group with a hydrogen ((±)-nornantenine) and an ethyl group at a nitrogen atom ((±)-ethylnornantenine) or introducing a hydroxyl group at the a/b position of C-4 or displacement of a methoxy moiety at the C-1 position with a hydroxyl ((±)-domesticine) of (±)-nantenine decreased the affinity. Moreover, changing a methyl group of (±)-domesticine to hydrogen at a nitrogen atom ((±)-nordomesticine) caused loss of the activities. These results suggest that a methyl group at a nitrogen atom and a methoxy moiety at C-1 play important roles in the development of the antiserotonergic activity. Molecular modeling analysis of the interaction between the 5-HT[sub2A] receptor and (±)-nantenine suggested that electron lone pairs of N-6 and of the oxygen atom of the methoxy group at C-1 are important in forming a hydrogen bond to Asp155 and Asn343 of the 5-HT[sub2A] receptor, respectively.
- Subjects
CHEMICAL structure; AMINO acids; BIOCHEMISTRY; HEART physiology; SEROTONINERGIC mechanisms
- Publication
Canadian Journal of Physiology & Pharmacology, 2002, Vol 80, Issue 3, p196
- ISSN
0008-4212
- Publication type
Article
- DOI
10.1139/y02-019