Linked Life Data

9484501

Source:http://linkedlifedata.com/resource/pubmed/id/9484501

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1998-3-17
pubmed:abstractText
A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6- dimethyl-3-nitro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity where the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et > MeOCH2CH2 > Me. The point of attachment of the C-4 pyridyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohexyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridyl)-5- pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist (IC50 = 5.27 x 10(-6) M) than the (-)-enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by (-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a new drug design concept directed toward the treatment of congestive heart failure, and for use as probes to study the structure-function relationships of calcium channels.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
509-14
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:9484501-Animals, pubmed-meshheading:9484501-Calcium Channel Agonists, pubmed-meshheading:9484501-Calcium Channel Blockers, pubmed-meshheading:9484501-Calcium Channels, pubmed-meshheading:9484501-Dihydropyridines, pubmed-meshheading:9484501-Guinea Pigs, pubmed-meshheading:9484501-Heart Atria, pubmed-meshheading:9484501-Heterocyclic Compounds, pubmed-meshheading:9484501-Ileum, pubmed-meshheading:9484501-Indicators and Reagents, pubmed-meshheading:9484501-Isomerism, pubmed-meshheading:9484501-Molecular Structure, pubmed-meshheading:9484501-Muscle, Smooth, pubmed-meshheading:9484501-Muscle Contraction, pubmed-meshheading:9484501-Myocardial Contraction, pubmed-meshheading:9484501-Pyridines, pubmed-meshheading:9484501-Stereoisomerism, pubmed-meshheading:9484501-Structure-Activity Relationship
pubmed:year
1998
pubmed:articleTitle
Synthesis and calcium channel-modulating effects of alkyl (or cycloalkyl) 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate racemates and enantiomers.
pubmed:affiliation
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't