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.
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.
Ramesh
M
M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Matowe
W C
WC
Akula
M R
MR
Vo
D
D
Dagnino
L
L
Li-Kwong-Ken
M C
MC
Wolowyk
M W
MW
Knaus
E E
EE
D000818:Animals; D002120:Calcium Channel Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007536:Isomerism; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C110782:1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D011725:Pyridines