Structure-activity relationship on (+/-)-nantenine derivatives in antiserotonergic activities in rat aorta.
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 alpha/beta 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-HT2A 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-HT2A receptor, respectively.
Indra
Bachtiar
B
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Sendai, Japan.
Matsunaga
Kimihiro
K
Hoshino
Osamu
O
Suzuki
Masaji
M
Ogasawara
Hiromichi
H
Ishiguro
Masaji
M
Ohizumi
Yasushi
Y
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D001060:Aporphines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005625:Frontal Lobe / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001060:Aporphines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C041615:nantenine