The Ca2+ channel drugs, including the clinically available verapamil, nifedipine and diltiazem, enjoy prominent use both as therapeutic agents in the control of number of cardiovascular disorders, but also as molecular probes with which to analyze the structure and function of voltage- dependent Ca2+ channels. Much remains to be established concerning the underlying sites and mechanisms of action of these agents, both antagonists and activators. Synthetic chemical, radioligand binding and pharmacologic approaches will be used to obtain a number of related objectives with particular references to 1,4-dihydropyridines. a. A systematic exploration of the structure-activity relationship of the 1,4-dihydropyridine binding site to map out the geometries and energetics of the binding surface. Radioligand binding, tissue pharmacology and 45Ca2+ uptake studies will characterize biological effects of both activators and antagonists. b. Synthesis of irreversible probes - to characterize relationship between channel number and response and to define location of 1,4-DHP binding sites. c. Synthesis of probes to aid in the physical localization of drug molecules d. Measurement of turnover rates of Ca2+ channels and associated probes e. Analysis of homologous and heterologous regulation of Ca2+ channel function by drugs and hormones f. Identification of the role of membrane potential and G protein activation on the affinities of drugs and receptor sites I anticipate that these approaches will be of use to determine the molecular basis of selectivity of action of Ca2+ channel ligands in physiological and pathological states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016003-20
Application #
3335095
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1977-05-01
Project End
1992-12-31
Budget Start
1991-04-01
Budget End
1992-12-31
Support Year
20
Fiscal Year
1991
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Schools of Pharmacy
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
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Rojstaczer, N; Triggle, D J (1996) Structure-function relationships of calcium antagonists. Effect on oxidative modification of low density lipoprotein. Biochem Pharmacol 51:141-50
Zheng, W; Feng, G; Ren, D et al. (1995) Cloning and characterization of a calcium channel alpha 1 subunit from Drosophila melanogaster with similarity to the rat brain type D isoform. J Neurosci 15:1132-43
Bangalore, R; Triggle, D J (1995) Age-dependent changes in voltage-gated calcium channels and ATP-dependent potassium channels in Fischer 344 rats. Gen Pharmacol 26:1237-42
Sun, J; Triggle, D J (1995) Calcium channel antagonists: cardiovascular selectivity of action. J Pharmacol Exp Ther 274:419-26
Liu, J; Rutledge, A; Triggle, D J (1995) Short-term regulation of neuronal calcium channels by depolarization. Ann N Y Acad Sci 765:119-33;discussion 160-2
Liu, J; Bangalore, R; Rutledge, A et al. (1994) Modulation of L-type Ca2+ channels in clonal rat pituitary cells by membrane depolarization. Mol Pharmacol 45:1198-206
Baindur, N; Triggle, D J (1994) Concepts and progress in the development and utilization of receptor-specific fluorescent ligands. Med Res Rev 14:591-664
Baindur, N; Rutledge, A; Triggle, D J (1993) A homologous series of permanently charged 1,4-dihydropyridines: novel probes designed to localize drug binding sites on ion channels. J Med Chem 36:3743-5
Bauer, J A; Fung, H L; Zheng, W et al. (1993) Continuous versus intermittent nitroglycerin administration in experimental heart failure: vascular relaxation and radioligand binding to adrenoceptors and ion channels. J Cardiovasc Pharmacol 22:600-8

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