Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylates

Lina Dagnino, Moy Cheong Li-Kwong-Ken, Michael W. Wolowyk, Christopher Triggle, Edward E. Knaus

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Reaction of dialkyl 1′,4′-dihydro-2′,6′-dimethyl[bipyridine]-3′,5′-dicarboxylates 2 with methyl iodide yielded the corresponding 4′-(1-methylpyridinium) iodide salts 3 in quantitative yield. The sodium borohydride reduction of 3 in aqueous ethanol gave the corresponding dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylate analogs 4-5. The calcium channel antagonist activities for 4-5 were determined using the muscarinic receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activities for the 3′,5′-diethyl series 5 was 3-tetrahydropyridinyl 5b > 4-tetrahydropyridinyl 5c > 2-tetrahydropyridinyl 5a. Increasing the size of the 3′,5′-alkyl substituents enhanced activity. An approximate 1:1 correlation between the IC50 value for the inhibition of [3H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed for 4a and 5b. NMR studies suggest that the 4′-[2-(1-methyl-1,2,3,6-tetrahydropyridinyl)] ring systems of 4a and 5a are anti-periplanar to the 1,4-dihydropyridine ring system.

Original languageEnglish
Pages (from-to)499-503
Number of pages5
JournalEuropean Journal of Medicinal Chemistry
Volume22
Issue number6
DOIs
Publication statusPublished - 1987
Externally publishedYes

Fingerprint

Nitrendipine
Calcium Channel Blockers
Muscarinic Receptors
Cholinergic Agents
Inhibitory Concentration 50
Smooth Muscle
Muscle
Guinea Pigs
Ethanol
Salts
Nuclear magnetic resonance
methyl iodide
1-methylpyridinium
1,4-dihydropyridine
sodium borohydride
4-methylpyridine

Keywords

  • 1,4-dihydropyridines
  • anti-hypertensives
  • calcium channel antagonists
  • vasodilators

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylates. / Dagnino, Lina; Li-Kwong-Ken, Moy Cheong; Wolowyk, Michael W.; Triggle, Christopher; Knaus, Edward E.

In: European Journal of Medicinal Chemistry, Vol. 22, No. 6, 1987, p. 499-503.

Research output: Contribution to journalArticle

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