(+/-)-Domesticine, a novel and selective alpha1D-adrenoceptor antagonist in animal tissues and human alpha 1-adrenoceptors

Eur J Pharmacol. 2002 Jun 7;445(1-2):21-9. doi: 10.1016/s0014-2999(02)01601-1.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / metabolism
  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Aporphines / chemistry
  • Aporphines / metabolism
  • Aporphines / pharmacology*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Piperazines / pharmacology
  • Rabbits
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT1
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology


  • ADRA1D protein, human
  • Adra1d protein, rat
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Aporphines
  • Piperazines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • domesticine
  • BMY 7378