title: (+/-)-Domesticine, a novel and selective alpha1D-adrenoceptor antagonist in animal tissues and human alpha 1-adrenoceptors.
abstract: The pharmacological profile of (+/-)-domesticine, a novel alpha(1)-adrenoceptor antagonist, was examined in animal tissues and Chinese hamster ovary (CHO) cells expressing cloned human alpha(1)-adrenoceptor subtypes and compared with the properties of BMY-7378 ([8-(2-[4-(2-methoxy-phenyl)-1-piperazinyl]ethyl)-8-azaspirol [4.5]decane-7,9-dione dihydrochloride], the prototypical alpha(1D)-adrenoceptor antagonist. Both (+/-)-domesticine and BMY-7378 were more potent in inhibiting the phenylephrine-induced contraction in rat thoracic aorta than tail artery or spleen. The selectivity of (+/-)-domesticine to inhibit phenylephrine-induced contraction in rat thoracic aorta was 32- and 17-fold higher than that in tail artery and spleen, respectively, while that of BMY-7378 it was 125- and 11-fold, respectively. The functional affinity profiles of these compounds for the alpha(1)-adrenoceptor subtypes in animal tissues were consistent with the respective binding affinity profiles in cloned human alpha(1)-adrenoceptor subtypes. (+/-)-Domesticine displayed a 34- and 9-fold higher selectivity for alpha(1d)-adrenoceptor than for alpha(1a)- and alpha(1b)-adrenoceptor, respectively, while BMY-7378 showed a selectivity for alpha(1d)-adrenoceptor of 102-fold higher than that of alpha(1a)-adrenoceptor and 21-fold higher than that of alpha(1b)-adrenoceptor. Interestingly, in [3H]8-OH-DPAT (8-hidroxy-2-(di-n-propyl-amino)tetraline hidrobromide) binding to 5-HT(1A) receptors of rat cerebral cortex, (+/-)-domesticine showed a 183-fold higher selectivity for alpha(1D)-adrenoceptor relative to 5-HT(1A) receptor, whereas BMY-7378 displayed a similar affinity at this receptor with respect to the alpha(1D)-adrenoceptor (0.89-fold). Both compounds, however, showed a weak affinity for 5-HT(2A)/5-HT(2C) receptors in rat frontal cortex. These results suggest that (+/-)-domesticine is more potent for alpha(1D)-adrenoceptor than for alpha(1A)- or alpha(1B)-adrenoceptor subtypes and it is highly selective compared to 5-HT(1A) and other receptors.
authors.affiliation: Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba, 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: Ikunobu
authors.initials: I
authors.lastname: Muramatsu
authors.forename: Takanobu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001060:Aporphines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C547719:ADRA1D protein, human; C547721:Adra1d protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001060:Aporphines; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C454302:domesticine; C053428:BMY 7378