title: Structure-activity relationship studies with (+/-)-nantenine derivatives for alpha1-adrenoceptor antagonist activity.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Bachtiar
authors.initials: B
authors.lastname: Indra
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Osamu
authors.initials: O
authors.lastname: Hoshino
authors.forename: Masaji
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ogasawara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001060:Aporphines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D018674:Adrenergic Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D001060:Aporphines; D007295:Inositol Phosphates; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; C011686:boldine; C454302:domesticine; C041615:nantenine