Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety

D. A. Soboleski, Cheong Li-Kwong-Ken Moy Cheong Li-Kwong-Ken, H. Wynn, Christopher Triggle, M. W. Wolowyk, E. E. Knaus

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl > 3-trifluoromethyl(nitro)phenyl > 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5- dicarboxylates (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the 1-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3,5- dicarboxylates (9).

Original languageEnglish
Pages (from-to)177-189
Number of pages13
JournalDrug Design and Delivery
Volume2
Issue number3
Publication statusPublished - 1988
Externally publishedYes

Fingerprint

Calcium Channel Blockers
Nifedipine
Acetoacetates
Perchlorates
Dihydropyridines
Pyridines
Nitrendipine
Muscarinic Receptors
Calcium Channels
Aldehydes
Smooth Muscle
Guinea Pigs
Esters
Ethanol
1,4-dihydropyridine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Soboleski, D. A., Moy Cheong Li-Kwong-Ken, C. L-K-K., Wynn, H., Triggle, C., Wolowyk, M. W., & Knaus, E. E. (1988). Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety. Drug Design and Delivery, 2(3), 177-189.

Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety. / Soboleski, D. A.; Moy Cheong Li-Kwong-Ken, Cheong Li-Kwong-Ken; Wynn, H.; Triggle, Christopher; Wolowyk, M. W.; Knaus, E. E.

In: Drug Design and Delivery, Vol. 2, No. 3, 1988, p. 177-189.

Research output: Contribution to journalArticle

Soboleski, D. A. ; Moy Cheong Li-Kwong-Ken, Cheong Li-Kwong-Ken ; Wynn, H. ; Triggle, Christopher ; Wolowyk, M. W. ; Knaus, E. E. / Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety. In: Drug Design and Delivery. 1988 ; Vol. 2, No. 3. pp. 177-189.
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AU - Soboleski, D. A.

AU - Moy Cheong Li-Kwong-Ken, Cheong Li-Kwong-Ken

AU - Wynn, H.

AU - Triggle, Christopher

AU - Wolowyk, M. W.

AU - Knaus, E. E.

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N2 - Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl > 3-trifluoromethyl(nitro)phenyl > 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5- dicarboxylates (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the 1-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3,5- dicarboxylates (9).

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