Novel Hantzsch 1,4-dihydropyridines to study the structure-function relationships of calcium channels and photoinduced relaxation

Nadeem Iqbal, Christopher Triggle, Edward E. Knaus

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A group of methyl 1,4-dihydro-2,6-dimethyl-4-(2-, 3- or 4-NHOH; 3- or 4-N=O)-phenyl-5-pyridinecarboxylates possessing a C-3 CO2Me or NO2 substituent [compounds 5-8, 10-12, below] were synthesized by reduction of the C-4 nitrophenyl precursors [1-4] to the corresponding phenylhydroxylamine [5-8] derivatives using 5% rhodium-on-charcoal with hydrazine hydrate as the hydrogen donor, followed by re-oxidation of the phenylhydroxylamine product [6-8] to the corresponding ntrosophenyl [10-12] derivative using pyridinium chlorochromate. A series of 1,4-dihydro-2,6-dimethyl4-(2-trifluoromethylphenyl)pyridines [26-34] possessing CO2Me, COMe, CONH2, P(= O)OEt2, CN, NO2 C-3/C-5 substituents were synthesized using a modified Hantzsch reaction involving the condensation of 2-trifluoromethylbenzaldehyde [17] with an aminocrotonate [18-20] and a ketone [21-25] derivative. In vitro calcium channel (CC) activities were determined using a muscarinic-receptor-mediated Ca+2-dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds [5-8, 10-12, 26-34] exhibited weak CC antagonist activity [10-4 to 10-7 M range] relative to the reference drug nifedipine [IC50 = 1.4 x 10-8 M]. Structure-activity relationships [SARs] acquired were in agreement with known SARs where the relative potency order for C-4 phenyl substituents is ortho and meta > para. A C-3 nitro substituent decreased CC antagonist activity. Compounds 29-34 possessing C-3 CN or NO2, and a C-5 CO2Me, NO2, CONH2, COMe, or P(= O)OEt2, substituents exhibited weak CC antagonist activity in the 10-4 to 10-5 M range. Although this group of highly functionalized 1,4-dihydropyridines are not useful CC antagonists, they will serve as valuable model compounds to study the structure-function relationships of CC modulation.

Original languageEnglish
Pages (from-to)120-130
Number of pages11
JournalDrug Development Research
Issue number3-4
Publication statusPublished - Nov 1997
Externally publishedYes



  • 1,4-dihydropyridines
  • Calcium channel antagonists

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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