Abstract：
:Endothelins, 21-amino acid peptides involved in the pathogenesis of various diseases, bind to endothelin ET(A) and ET(B) receptors to initiate their effects. Here, we characterize the pharmacology of A-216546 ([2S-(2,2-dimethylpentyl)-4S-(7-methoxy-1,3-benzodioxol-5-yl )-1-(N,N-di(n-butyl) aminocarbonylmethyl)-pyrrolidine-3R-carboxylic acid), a potent antagonist with > 25,000-fold selectivity for the endothelin ET(A) receptor. A-216546 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptors competitively with Ki of 0.46 and 13,000 nM, and blocked endothelin-1-induced arachidonic acid release and phosphatidylinositol hydrolysis with IC50 of 0.59 and 3 nM, respectively. In isolated vessels, A-216546 inhibited endothelin ET(A) receptor-mediated endothelin-1-induced vasoconstriction, and endothelin ET(B) receptor-mediated sarafotoxin 6c-induced vasoconstriction with pA2 of 8.29 and 4.57, respectively. A-216546 was orally available in rat, dog and monkey. In vivo, A-216546 dose-dependently blocked endothelin-1-induced pressor response in conscious rats. Maximal inhibition remained constant for at least 8 h after dosing. In conclusion, A-216546 is a potent, highly endothelin ET(A) receptor-selective and orally available antagonist, and will be useful for treating endothelin-1-mediated diseases.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Wu-Wong JR,Dixon DB,Chiou WJ,Dayton BD,Novosad EI,Adler AL,Wessale JL,Calzadilla SV,Hernandez L,Marsh KC,Liu G,Szczepankiewicz B,von Geldern TW,Opgenorth TJdoi
10.1016/s0014-2999(98)00891-7keywords:
subject
Has Abstractpub_date
1999-02-05 00:00:00pages
189-201issue
2-3eissn
0014-2999issn
1879-0712pii
S0014-2999(98)00891-7journal_volume
366pub_type
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journal_title：European journal of pharmacology
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journal_title：European journal of pharmacology
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journal_title：European journal of pharmacology
pub_type： 杂志文章,评审
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journal_title：European journal of pharmacology
pub_type： 杂志文章
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