Molecular Pharmacology, Vol 20, 395-403, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Ferrochelatase-Inhibitory and Porphyrin-Inducing Properties of 3,5-Diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine and Its Analogues in Chick Embryo Liver Cells

¹ Departments of Pharmacology and Chemistry, Queen‘s University, Kingston, Ontario, Canada K7L 3N6

A series of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) was investigated for ferrochelatase-inhibitory and porphyrin-inducing activities in chick embryo liver cell cultures. It was found that, in order to inhibit ferrochelatase maximally, a DDC analogue must be a dihydropyridine with ester groups in positions 3 and 5, and an alkyl substituent in position 4. The structural requirements for porphyrin-inducing activity were less stringent. The pattern of porphyrin accumulation produced in response to DDC and its analogues was investigated using high-performance liquid chromatography. Protoporphyrin was found to be the major porphyrin to accumulate in response to dihydropyridine analogues that inhibited ferrochelatase. Uro- and heptacarboxylic porphyrins were the major porphyrins to accumulate in response to all of the pyridine analogues. A pattern of porphyrin accumulation very similar to that produced by the pyridine analogues was observed with those dihydropyridine analogues which did not inhibit ferrochelatase, suggesting that these dihydropyridines are readily converted to pyridines in the chick embryo liver cell culture. It is clear that some analogues of DDC induce porphyrin accumulation by a mechanism other than through ferrochelatase inhibition.

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ACKNOWLEDGMENTS The authors wish to thank Mr. Scott Follows, Ms. Frances Taylor, and Ms. Anne Weary for their able technical assistance. We are grateful to Ms. Debbie Browne for her help in the preparation of the manuscript.

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