In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist.
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.
Chang
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RS
Department of Pharmacology, Merck Research Laboratories, WP 46-300, P.O. Box 4, West Point, PA 19486-0004, USA. ray_chang@merck.com
Chen
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O'Malley
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Pettibone
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DiSalvo
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Francis
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Bock
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Freidinger
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Nagarathnam
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Miao
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Shen
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Lagu
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Murali Dhar
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Tyagarajan
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Marzabadi
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Wong
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Gluchowski
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Forray
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D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008297:Male; D010656:Phenylephrine / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism*; D011744:Pyrimidinones / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism
C094643:A 61603; C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D011744:Pyrimidinones; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D010656:Phenylephrine; C420450:L 771688; D011224:Prazosin