Summary
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1.
The effects on contractile activity of 2 series of nifedipine-derivatives were investigated in isolated, isotonically contracting cat papillary muscles.
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2.
For structure-activity studies the lipophilicity of all compounds was determined by means of reversed phase thin-layer chromatography.
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3.
Neither the ortho-NO2 group in a series of arylderivatives nor the methyl-esters in a series of esterderivatives were found to be essential for the typical effect of the nifedipine molecule on myocardial contractility.
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4.
Generally ortho-substituted derivatives induce a greater negative inotropic activity than meta-substituted derivatives. Para-substituted derivatives are the least active compounds.
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5.
In the group of ester-derivatives activity decreases when lipophilicity and/or volume of the substituent increases.
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6.
The quantitative analysis (Hansch analysis) revealed significant correlations between the negative inotropic effect and steric substituent parameters. Best correlations were obtained with:
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i)
the minimum width, B 1 (ortho-substituted derivatives);
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ii)
the van der Waals volume, V w (ester-substituted derivatives);
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iii)
the experimentally or theoretically determined lipophilicity, R M or π, respectively (ester-derivatives).
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7.
It is concluded that-within a group of nifedipine derivatives-the negative inotropic effect depends mainly on steric and on lipophilic and/or steric substituent properties for aryl- and ester-derivatives, respectively. Electronic influences are not important for the biological activity.
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This work was supported in part by grants of the Deutsche Forschungsgemeinschaft (SFB 30, Kardiologie)
Preliminary results were presented to the 19th meeting of the German Pharmacological Society, Mainz 1978 (Rodenkirchen et al., 1978)
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Rodenkirchen, R., Bayer, R., Steiner, R. et al. Structure-activity studies on nifedipine in isolated cardiac muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 310, 69–78 (1979). https://doi.org/10.1007/BF00499876
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DOI: https://doi.org/10.1007/BF00499876