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.