Summary
It has been reported that the lipophilicity of dihydropyridine-type calcium entry blockers may influence both their negative inotropic and their vasodilator activities. The action of nitrendipine and six related 3-ester side-chain derivatives with increasing alkyl and aryl substituents have been investigated in isolated porcine trabecular muscles and coronary artery rings. The lipophilicity of the drugs was determined by high-pressure liquid chromatography. In addition, some sterical parameters of the ester derivatives were considered. For the drugs tested, an increase in 3-ester side chain volume correlated well with increasing lipophilicity. Compared to nitrendipine, vascular selectivity of the ester side-chain derivatives, as expressed by the ratio of their negative inotropic and vasodilator activities, was much reduced. Neither vasodilator nor negative inotropic activity was directly related to the corresponding lipophilicity. Based on these results, earlier suggestions about the influence of the ester side-chain in dihydropyridines on their cardiovascular profile are extended.
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References
Alker D, Campbell SF, Cross PE, Burges RA, Carter AJ, Gardiner DG (1989) Long-acting dihydropyridine calcium antagonists. 3. Synthesis and structure-activity relationships for a series of 2-((heterocyclylmethoxy)methyl)-derivatives. J Med Chem 32:2381–2388
Arrowsmith JE, Campbell SF, Cross PE, Burges RA, Gardiner DG (1989) Long-acting dihydropyridine calcium antagonists. 2. (2-(heterocycloethoxy)methyl)-derivatives. J Med Chem 32:562–568
Bean BP (1984) Nitrendipine block of cardiac calcium channels: high binding to the inactivated state. Proc Natl Acad Sci USA 81:6388–6392
Bolton TB, Kitamura K, Morel N (1983) Use dependent effects of calcium entry blocking on the electrical mechanical activities of guinea pig taenia caeci. Br J Pharmacol 78:174P
Bossert F, Horstmann H, Meyer H, Vater W (1979) Einfluss der Esterfunktion auf die vasodilatierenden Eigenschaften von 1,4-Dihydro-2,6-dimethyl-4-nitrophenyl-pyridin-3,5-dicarbon-saureestern. Arzneim Forsch 29:226–229
Brown AU, Morimoto K, Tsuda Y, Wilson DL (1981) Calcium-current dependent and voltage-dependent inactivation of calcium channels in Helix aspersa. J Physiol 320:193–218
Ehara T, Kaufmann R (1978) The voltage- and time-dependent effects of (−)-verapamil on the slow inward current in isolated cat ventricular myocardium. J Pharmacol Exp Ther 207:49–55
Fricke U, Klaus W, Stein B (1988) Novel halogenated dihydropyridine derivatives with high vascular selectivity. Naunyn-Schmiedberg's Arch Pharmacol 338:449–454
Fricke U, Ückert M (1988) Effects of nimodipine, nisoldipine and halogenated derivatives of nitrendipine in isolated arteries and ventricular muscles of the pig. Naunyn-Schmiedeberg's Arch Pharmacol 338 [Suppl]:R36
Fricke U, Klaus W, Werner G, Kojda G (1989) Influence of nitrendipine 3-ester side chain variation on myocardial and vascular activity in porcine isolated tissue. Naunyn-Schmiedeberg's Arch Pharmacol 340 [Suppl]:R54
Gelmers HJ, Garter K, de Weerdt CJ, Wieser HJA (1985) Efficacy of treatment with nimodipine (calcium antagonist) in patients with acute ischemic stroke; a placebo-controlled double-blind, randomized, multicentre trial. J Cereb Blood Flow Metab 5 [Suppl I]: S337-S338
Godfraind T, Miller RC, Wibo M (1986) Calcium antagonism and calcium entry blockade. Pharm Rev 38:321–416
Godfraind T, Engleme C, Finet M, Jaumin O (1987a) The actions of nifedipine and nisoldipine on the contractile activity of human coronary arteries and human cardiac tissue in vitro. Pharmacol Toxicol 61:79–84
Godfraind T, Engleme C, Finet M, Debande B, Jaumin P (1987b) Comparison of nifedipine and nisoldipine on human arteries and human cardiac tissues in vitro. In: Hugenholtz PG, Meyer J (eds) Nisoldipine. Springer, Berlin Heidelberg New York, pp 36–44
Goll A, Glossmann H, Mannhold R (1986) Correlation between the negative inotropic potency and binding parameters of 1,4-dihydropyridine and phenylalkylamine calcium channel blockers in cat heart. Naunyn-Schmiedeberg's Arch Pharmacol 334:303–312
Hafner D, Heinen E, Noack E (1977) Mathematical analysis of concentration response relationships. Arzneim Forsch 27:1871–1873
Haky JE, Young AM (1984) Evaluation of a simple HPLC correlation method for the estimation of the octanol-water partition coefficients of organic compounds. J Liquid Chrom 7:675–689
Hess P, Lansman JB, Tsien RW (1984) Different modes of calcium channel gating behaviour favoured by dihydropyridine calcium agonists and antagonists. Nature 311:538–544
Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor interaction. J Gen Physiol 69:497–515
Karasawa A, Kubo K, Shuto K, Oka T, Nakamizo (1988) Pharmacological actions of benidipine hydrochloride in several isolated smooth muscles and myocardium. Arzneim Forsch 38:1722–1730
Kazda S, Towart R (1981) Differences in the effects of the calcium antagonists nimodipine (BAY E9736) and benzyclane on cerebral and peripheral smooth muscle. Br J Pharmacol 72:582P-583P
Lee KS, Tsien RW (1983) Mechanisms of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialyzed heart cells. Nature 302:790–794
Ljung G, Nordlander M (1987) Pharmacodynamic properties of felodipine. Drugs 34 [Suppl 3]:7–15
Mannhold R, Rodenkirchen R, Bayer R (1982) Qualitative and quantitative structure-activity relationships of specific calcium antagonists. Progr Pharmacol 5:25–52
McDonald T, Pelzer D, Trautwein W (1980) On the mechanism of slow calcium channel block in heart. Pflügers Arch 385:175–179
Meyer H, Bossert F, Wehinger E, Stoepel K, Vater W (1981) Synthese und vergleichende pharmakologische Untersuchungen von 1,4-Dihydro-2,6-dimethyl-4(3-nitrophenyl)-pyridin-3,5-dicarbonsaureestern mit nicht identischen Esterfunktionen. Arzneim Forsch 31: 407–409
Olivara MT, Levine TB, Cohn JN (1984) Acute hemodynamic effects of nitrendipine in chronic congestive heart failure. J Cardiovasc Pharmacol 6 [Suppl 7]:S1002-S1005
Pepine C (1989) Nicardipine, a new calcium channel blocker: role for vascular selectivity. Clin Cardiol 12:240–246
Reuter H (1984) Electrophysiology of calcium channel in the heart. In: Opie LH (ed) Calcium antagonists and cardiovascular disease. Raven Press, New York, pp 43–51
Rhodes DG, Sarmiento JG, Herbette LG (1985) Kinetics of binding of membrane active drugs to receptors. Diffusion limited rates for a membrane bilayer approach of 1,4-dihydro-pyridine calcium channel antagonists to their active site. Mol Pharmacol 27:612–623
Rodenkirchen R, Bayer R, Steiner R, Bossert F, Meyer H, Moeller E (1979) Structure-activity studies on nifedipine on isolated cardiac muscle. Naunyn-Schmiedeberg's Arch Pharmacol 310:69–78
Rutsch W, Schmutzler H (1984) Comparison of the acute hemodynamic effects of nitrendipine and a study of the electrophysiological effects of nitrendipine in man. J Cardiovasc Pharmacol 6 [Suppl7]: S1011-S1015
Sanguinetti MC, Kass RS (1984a) Voltage dependent block of calcium current in calf purkinje fibres by dihydropyridine calcium channel antagonists. Circ Res 55:336–348
Sanguinetti MC, Kass RS (1984b) Regulation of cardiac calcium current and contractile activity by the dihydropyridine BAY K 8644 is voltage dependent. J Moll Cell Cardiol 16:667–670
Su CM, Yousif FB, Triggle DJ, Janis RA (1985) Structure function relationships of 1,4-dihydropyridines: ligand and receptor perspectives. In: Fleckenstein A, Van Breemen C, Groß R, Hoffmeister F (eds) Cardiovascular effects of dihydropyridine type calcium antagonists and agonists. Springer, Berlin Heidelberg New York, pp 104–110
Towart R (1982) A new method for investigating the isometric contractile response of small blood vessels. Br J Pharmacol 75:150P
Trautwein W, Pelzer D, McDonald TF, Osterrieder D (1981) AQA39, a new bradycardiac agent, which blocks myocardial calcium channels in a frequency and voltage dependent manner. Naunyn-Schmiedeberg's Arch Pharmacol317:228–232
Triggle DJ, Janis RA (1984a) Nitrendipine: binding sites and mechanism of action. In: Scriabine A, Vanov S, Deck K (eds) Nitrendipine. Urban & Schwarzenberg, Baltimore München, pp 33–52
Triggle DJ, Janis RA (1984b) The 1,4-dihydropyridine receptor: a regulatory component of the calcium channel. J Cardiovasc Pharmacol 6 [Suppl]:S949-S955
Triggle DJ, Janis RA (1987) Calcium channel ligands. Ann Rev Pharmacol Toxicol 27:347–369
Triggle DJ, Langs DA, Janis RA (1989) Calcium channel ligands: structure-function relationships of the 1,4-dihydropyridines. Med Res Rev 9:123–180
Verloop A, Hoogenstraten W, Tipker J (1976) Development and application of new steric substituent parameters in drug design. In: Ariens EJ (ed) Drug design, vol VII. Academic Press, New York, pp 165–207
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Kojda, G., Klaus, W., Werner, G. et al. The influence of 3-ester side chain variation on the cardiovascular profile of nitrendipine in porcine isolated trabeculae and coronary arteries. Naunyn-Schmiedeberg's Arch Pharmacol 344, 488–494 (1991). https://doi.org/10.1007/BF00172590
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DOI: https://doi.org/10.1007/BF00172590