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



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



Drug Development Research. 42(3-4): 120-130,.-.



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 nitrosophenyl (10-12) derivative using pyridinium chlorochromate. A series of 1,4-dihydro-2,6-dimethyl-4-(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.

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Accession: 009110232

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DOI: 10.1002/(sici)1098-2299(199711/12)42:3/4<120::aid-ddr3>3.0.co;2-s


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