Correlation between pregnanesteroid conformation, receptor affinity, and anti-natriuretic effect.
The aim of this study was to correlate mineralocorticoid action and steroid structure. Inasmuch as Na(+) retention follows a parabolic dose-response curve for most pregnanesteroids, the second-order coefficient of the function was used as a representative factor for this bipartite biological effect. The C(3)=O/D angle of the ligands was correlated with both Na(+)-retaining activity and binding affinity for the mineralocorticoid receptor. Because some steroids exhibit identical functional groups and different conformational structure, we also postulate that the flat conformation of a pregnanesteroid determines its Na(+)-retaining capacity in vivo. No correlations were found in vitro, which demonstrates the multifactorial nature of the second-order coefficient determined in vivo under more complex and interactive conditions that include various pre-receptor variables. These findings may allow the estimation of the putative biological activity of a given steroid simply by knowing its conformational structure, which may be important for designing compounds in a pharmaceutical setting.
Piwien-Pilipuk
Graciela
G
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and PRHOM-CONICET, 1428 Buenos Aires, Argentina.
Kanelakis
Kimon C
KC
Galigniana
Mario D
MD
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D011278:Pregnanes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011278:Pregnanes; D018161:Receptors, Mineralocorticoid