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In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2000 Dec 15; Vol. 409 (3), pp. 301-12. - Publication Year :
- 2000
-
Abstract
- L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.
- Subjects :
- Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Agonists metabolism
Animals
Dogs
Humans
Imidazoles metabolism
Male
Phenylephrine metabolism
Prazosin analogs & derivatives
Rats
Tetrahydronaphthalenes metabolism
Urinary Bladder metabolism
Adrenergic alpha-Antagonists metabolism
Prazosin metabolism
Prostate metabolism
Pyrimidinones metabolism
Receptors, Adrenergic, alpha-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 409
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11108825
- Full Text :
- https://doi.org/10.1016/s0014-2999(00)00854-2