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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
26
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pubmed:dateCreated |
1999-1-21
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pubmed:abstractText |
We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ADRA1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Adra1a protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic alpha-1 Receptor...,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic alpha-Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Dihydropyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha-1,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BranchekT ATA,
pubmed-author:BrotenTT,
pubmed-author:ChangR SRS,
pubmed-author:ChiuGG,
pubmed-author:FangJJ,
pubmed-author:ForrayCC,
pubmed-author:GluchowskiCC,
pubmed-author:HeydornW EWE,
pubmed-author:HoogGG,
pubmed-author:MarzabadiM RMR,
pubmed-author:MiaoS WSW,
pubmed-author:NagarathnamDD,
pubmed-author:SchornT WTW,
pubmed-author:WetzelJ MJM,
pubmed-author:WongW CWC
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pubmed:issnType |
Print
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pubmed:day |
17
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5320-33
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:9857099-Adrenergic alpha-1 Receptor Antagonists,
pubmed-meshheading:9857099-Adrenergic alpha-Antagonists,
pubmed-meshheading:9857099-Animals,
pubmed-meshheading:9857099-Binding, Competitive,
pubmed-meshheading:9857099-Blood Pressure,
pubmed-meshheading:9857099-Cell Line,
pubmed-meshheading:9857099-Dihydropyridines,
pubmed-meshheading:9857099-Dogs,
pubmed-meshheading:9857099-Drug Evaluation, Preclinical,
pubmed-meshheading:9857099-Humans,
pubmed-meshheading:9857099-Male,
pubmed-meshheading:9857099-Muscle, Smooth,
pubmed-meshheading:9857099-Muscle Contraction,
pubmed-meshheading:9857099-Piperidines,
pubmed-meshheading:9857099-Prostate,
pubmed-meshheading:9857099-Prostatic Hyperplasia,
pubmed-meshheading:9857099-Rats,
pubmed-meshheading:9857099-Receptors, Adrenergic, alpha-1,
pubmed-meshheading:9857099-Recombinant Proteins,
pubmed-meshheading:9857099-Stereoisomerism,
pubmed-meshheading:9857099-Structure-Activity Relationship
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pubmed:year |
1998
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pubmed:articleTitle |
Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia.
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pubmed:affiliation |
Departments of Chemistry, Pharmacology, and Pharmaceutical Operations, Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.
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pubmed:publicationType |
Journal Article,
In Vitro
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