The group of compounds known as the CA++ channel antagonists and including the clinically available verapamil, nifedipine and diltiazem enjoy considerable pharmacologic and clinical attention. These agents and their analogs are believed to interact via a variety of mechanisms at voltage-dependent Ca++ channels. Several experimental approaches are planned to probe these Ca++ channels in smooth, cardiac and neuronal tissue. New Ca++ antagonists will be synthesised to investigate whether Ca++ channels can be differentiated into subtypes. The regulation of Ca++ channels including studies in developing and aging tissues, will be analysed. Through fluorescent analogs an attempt will be made to localize Ca++ channels. Possible changes in Ca++ and Ca++ antagonist sensitivity in the normo- and hypertensive state will be examined in several hypertensive models. An effort, will be made to synthesise """"""""site directed"""""""" Ca++ antagonists that will permit delivery of antagonists to specific receptors. Since their introduction into clinical medicine in North America, the available Ca++ antagonists have received considerable attention. Further understanding of their actions, as outlined here, will be of particular importance to the design of new and more selective agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016003-14
Application #
3335090
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1977-05-01
Project End
1988-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
14
Fiscal Year
1985
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
Peri, R; Padmanabhan, S; Rutledge, A et al. (2000) Permanently charged chiral 1,4-dihydropyridines: molecular probes of L-type calcium channels. Synthesis and pharmacological characterization of methyl(omega-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodid J Med Chem 43:2906-14
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
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
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
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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