title: Pharmacological evaluation of N-methyl-actinodaphnine, a new vascular alpha-adrenoceptor antagonist, isolated from Illigera luzonensis.
abstract: The pharmacological activity of N-methyl-actinodaphnine, isolated from Illigera luzonensis, was determined by functional and binding experiments with peripheral tissues. In a functional study, N-methyl-actinodaphnine was a simple competitive antagonist of contractions elicited by phenylephrine (pA2 = 7.11) in rat thoracic aorta; it also competitively antagonised the clonidine-induced inhibition of the twitch response of rat vas deferens (pA2 = 5.01). In addition, [3H]inositol monophosphate formation caused by noradrenaline (3 microM) in rat isolated thoracic aorta was concentration dependently inhibited by N-methyl-actinodaphnine (1 and 10 microM); however, it had no effect on cyclic AMP and cyclic GMP contents. Additionally, N-methyl-actinodaphnine had extremely low affinity for thromboxane receptors, prostaglandin receptors, Ca2+ channels, muscarinic receptors, histamine receptors, beta-adrenoceptors, neurokinin and leukotriene receptors in vitro. However, N-methyl-actinodaphnine also possessed 5-hydroxytryptamine (5-HT) receptor blocking activity. Its potency for blocking 5-HT receptors was about 14 times less than that for blocking alpha 1-adrenoceptors. In binding experiments, N-methyl-actinodaphnine displaced biphasically the binding of 0.2 nM [3H]prazosin to cultured A10 cells. The selectivity for alpha 1-adrenoceptor subtypes was also investigated in rat vas deferens and spleens. The contractile response in rat vas deferens to noradrenaline was competitively inhibited by N-methyl-actinodaphnine with a pA2 value of 6.58; N-methyl-actinodaphnine also competitively antagonized the phenylephrine-induced contraction in rat spleen with a pA2 value of 7.38. These results indicate that N-methyl-actinodaphnine is a selective alpha 1-adrenoceptor antagonist. Furthermore, it is more selective for the alpha 1B- than for the alpha 1A-adrenoceptor subtype.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
authors.forename: J H
authors.initials: JH
authors.lastname: Guh
authors.forename: F N
authors.initials: FN
authors.lastname: Ko
authors.forename: S M
authors.initials: SM
authors.lastname: Yu
authors.forename: Y C
authors.initials: YC
authors.lastname: Wu
authors.forename: C M
authors.initials: CM
authors.lastname: Teng
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002478:Cells, Cultured; D004148:Dioxolanes / Q000302:isolation & purification / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007295:Inositol Phosphates / Q000032:analysis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects; D014132:Trachea / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004148:Dioxolanes; D004365:Drugs, Chinese Herbal; D007295:Inositol Phosphates; C096158:N-methylactinodaphnine; D010879:Piperazines; C057446:5-methylurapidil; D011224:Prazosin