Structure-activity relationship studies with (±)-nantenine derivatives for α1-adrenoceptor antagonist activity

A series of (+/-)-nantenine derivatives of the natural aporphine alkaloids was synthesized and examined for a blocking action on a, adrenoceptors in rat aorta and A10-cells. The potency of these derivatives was compared with that of an aporphine-related compounds (+)boldine, an alpha(1)-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 ot alpha(1) -adrenoceptor-blocking action. The order of pA(2) 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 (+/-)-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 alpha(1)-adrenoceptor. (C) 2002 Elsevier Science B.V. All rights reserved.