Linked Life Data

2896246

Source:http://linkedlifedata.com/resource/pubmed/id/2896246

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1988-6-7
pubmed:abstractText
Treatment of 2-methyl-4,5-dimethoxybenzonitrile (3) with LDA followed by reaction with an N,N-disubstituted cyanamide provided a series of 1,3-diamino-6,7-dimethoxyisoquinolines (2), which were evaluated for alpha-adrenoceptor binding affinity and antihypertensive activity. 1-Amino-3-(dimethylamino)-6,7-dimethoxyisoquinoline (4) showed no significant affinity (Ki much greater than 10(-6) M) for alpha 1-adrenoceptors, while the corresponding 3-(2-furoylpiperazin-1-yl) analogue (8; Ki = 1.6 X 10(-7) M) was some 1000-fold less potent than prazosin. pKa data showed that N-2 protonation (34%) of 4 (pKa = 7.1) would occur at physiological pH, in agreement with X-ray crystallographic analysis of 8.HCl. Comparison of positive charge distribution following protonation of 4 with the corresponding quinoline and quinazoline cations confirmed N-1 protonation is required for these heterocyclic nuclei to bind efficiently to the alpha 1-adrenoceptor. Computer-assisted comparison of the X-ray structures of 8 and prazosin suggested that the 4.0 kcal/mol difference in alpha 1-adrenoceptor binding energies was largely due to salt-bridge formation (ca. 3.0 kcal/mol) between the protonated quinazoline and the receptor protein. None of the isoquinolines (2) proved to be effective antihypertensive agents in rats even when administered at relatively high doses (10 mg/kg). These results support the hypothesis that the antihypertensive activity of prazosin, doxazosin, and related derivatives derives solely from alpha 1-adrenoceptor blockade.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1036-9
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
1988
pubmed:articleTitle
1,3-Diamino-6,7-dimethoxyisoquinoline derivatives as potential alpha 1-adrenoceptor antagonists.
pubmed:affiliation
Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, United Kingdom.
pubmed:publicationType
Journal Article, In Vitro