Structure-activity relationship studies with (+/-)-nantenine derivatives for alpha1-adrenoceptor antagonist activity.

A series of (+/-)-nantenine derivatives of the natural aporphine alkaloids was synthesized and examined for a blocking action on alpha1-adrenoceptors in rat aorta and A10-cells. The potency of these derivatives was compared with that of an aporphine-related compounds (+)-boldine, an alpha1-adrenoceptor antagonist. Among nine (+/-)-nantenine derivatives having different substituents at N-6, C-1, or C-4 of the aporphine skeleton, (+/-)-domesticine had the most powerful alpha1-adrenoceptor-blocking action. The order of pA2 values was (+/-)-domesticine (8.06+/-0.06)>(+/-)-nordomesticine (7.34+/-0.03)>(+/-)-nantenine (7.03+/-0.03)>(+)-boldine (6.91+/-0.02)>other derivatives. Study of the structure-activity relationships showed that the replacement of a methoxy moiety at C-1 position of (plus minus)-nantenine with a hydroxyl group increased affinity for the receptor. In contrast, replacement of a methyl group with a hydrogen atom or an ethyl group at N-6 position in the (+/-)-nantenine structure decreased affinity for the receptor. These results suggest that a hydroxyl group at the C-1 position and a methyl group at the N-6 position in the (+/-)-nantenine structure are essential for the enhancement of affinity for the alpha1-adrenoceptor.