Summary
An investigation was carried out towards a qualitative and quantitative structure-activity relationship of verapamil based on an analysis of the frequency-dependent negative inotropic action exerted in cat papillary muscles by various groups of verapamil derivatives.
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(1)
Substituents of the benzene ring near the asymmetric carbon atom and the isopropyl group were found to be no essential substituents for the frequency-dependent negative inotropic acition of verapamil but to have a strong influence on the potency of the drug.
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(2)
Both the tertiary amino nitrogen and the two benzene rings are essential for the frequency-dependent negative inotropic action of verapamil.
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(3)
The molecular importance of the N-methyl group is probably based on steric effects.
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(4)
Investigations of the verapamil derivative H 1 revealed that a quaternization of the drug is followed by a total loss of effectiveness.
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(5)
No significant correlation of the biological activity of verapamil derivatives with the partition coefficient P has been obtained.
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(6)
Hansch analysis with verapamil derivatives of group A (= diferent substitution of the benzene ring near C*) shows that the variance of biological activity can be optimally correlated to a combination of the Hammett constant and the molar volume. Hansch analysis of group B (= exchange of isopropyl group) led to the conclusion that hydrophobic effects are responsible for the influence of the isopropyl substituent.
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Bayer, R., Hennekes, R., Kaufmann, R., Mannhold, R.: Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. I. Pattern of inotropic effects of the racemic compounds. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 49–68 (1975a)
Bayer, R., Kaufmann, R., Mannhold, R.: Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. II. Pattern of inotropic effects of the optical isomers. Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 69–80 (1975b)
Bayer, R., Rodenkirchen, R., Ehara, T., Mannhold, R.: Comparative studies of inotropic and electrophysiological effects of “slow channel inhibitors” in isolated mammalian cardiac muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. Suppl. 293, R21 (1976)
Bleeker, A.: The mechanism of the cardiodepressive effect of (±)-verapamil (Isoptin®). Thesis, Amsterdam 1977
Craig, P. N.: Interdependence between physical parameters and selection of substituent groups for correlation studies. J. Med. Chem. 14, 680–684 (1971)
Exner, O.: Dipole moments in organic chemistry, p. 33. Stuttgart: Thieme Verlag 1975
Fujita, T., Iwasa, J., Hansch, C.: A new substituent constant, π, derived from partition coefficients. J. Am. Chem. Soc. 86, 5175–5180 (1964)
Hansch, C., Fujita, T.: ϱ-σ-π analysis. A method for the correlation of biological activity and chemical structure. J. Am. Chem. Soc. 86, 1616–1626 (1964)
Hansch, C., Leo, A., Unger, S. H., Kim, K. H., Nikaitani, D., Lien, E. J.: “Aromatic” substituent constants for structure-activity correlations. J. Med. Chem. 16, 1207–1216 (1973)
Hansch, C., Muir, R. M., Fujita, T., Maloney, P. P., Geiger, F., Streich, M.: The correlation of biological activity of plant growth regulators and chloromycetin derivatives with Hammett constants and partition coefficients. J. Am. Chem. Soc. 85, 2817–2824 (1963)
Hansch, C., Steward, A. R., Anderson, S. M., Bentley, D. L.: The parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics. J. Med. Chem. 11, 1–11 (1968)
Hellenbrecht, D., Lemmer, B., Wiethold, G., Grobecker, H.: Measurement of hydrophobicity, surface activity, local anaesthesia and myocardial conduction velocity as quantitative parameters of the non-specific membrane affinity of nine β-adrenergic blocking agents. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 211–226 (1973)
Kaufmann, R., Lab, M. J., Hennekes, R., Krause, H.: Feedback interaction of mechanical and electrical events in the isolated mammalian ventricular myocardium (cat papillary muscle). Pflügers Arch. 324, 100–123 (1971)
Kubinyi, H.: Quantitative structure-activity relationships. IV. Nonlinear dependence of biological activity on hydrophobic character: a new model. Arzneim.-Forsch. 26, 1991–1997 (1976)
Leo, A., Hansch, C., Church, C.: Comparison of parameters currently used in the study of structure-activity relationships. J. Med. Chem. 12, 766–771 (1969)
Mannhold, R., Bayer, R.: Towards a structure-activity relationship of “slow channel inhibitors”. Comparative studies of inotropic patterns exerted by some derivatives of verapamil. Naunyn-Schmiedeberg's Arch. Pharmacol. Suppl. 293, R83 (1976)
McFarland, J. W.: On the parabolic relationship between drug potency and hydrophobicity. J. Med. Chem. 13, 1192–1196 (1970)
McFarland, J. W.: On the understanding of drug potency. Prog. Drug. Res. 15, 123–146 (1971)
Staab, H. A.: Einführung in die theoretische organische Chemie. 4. Auflage, p. 216. Weinheim/Bergstrasse: Verlag Chemie 1970
Taft, jr., R. W.: Separation of polar, steric, and resonance effects. In: Newman, M. S.: Steric effects in organic chemistry, p. 586, New York. Wiley & Sons 1956
Topliss, J., Costello, R. J.: Chance correlations in structure-activity studies using multiple regression analysis. J. Med. Chem. 15, 1066–1068 (1972)
Unger, S., Hansch, C.: On model building in structure-activity relationships. A reexamination of adrenergic blocking activity of β-halo-β-arylalkylamines. J. Med. Chem. 16, 745–749 (1973)
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This work was supported in part by grants of the Deutsche Forschungsgemeinschaft (SFB 30, Cardiologie).
Preliminary results of this study were already presented to the 17th spring meeting of the German Pharmacological Society, Mainz 1976 (Mannhold and Bayer, 1976).
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Mannhold, R., Steiner, R., Haas, W. et al. Investigations on the structure-activity relationships of verapamil. Naunyn-Schmiedeberg's Arch. Pharmacol. 302, 217–226 (1978). https://doi.org/10.1007/BF00517988
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DOI: https://doi.org/10.1007/BF00517988