Molecular Pharmacology, Vol 18, 402-405, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Progesterone Derivatives that Bind to the Digitalis Receptor: Structure-Activity Relationships

¹ Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada, R3E 0W3
² Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada, R3T 2N2

Certain progesterone derivatives compete for binding in a cardiac glycoside radioreceptor assay. Systematic examination of structurally modified progesterones shows that substitution and/or unsaturation in the B ring of the steroid nucleus and the presence of 17-acetoxy are important determinants of binding potency. Although 17-acetoxyprogesterone itself is very weak, substitution of that steroid at C-6 by either 6-methyl, 6-chloro, or 6-bromo groups markedly enhanced receptor binding. This effect may be due to the long-range influence of 17-acetate plus the steric strain introduced by 6-substitution which lead to inversion of the A ring to a digitalis-like conformation. Substitution plus unsaturation at C-6 appear to be more important than either alone, as indicated by the highly potent chlormadinone acetate, bromadinone acetate, and megestrol acetate. Steric rather than electronic effects are operative in the potency enhancing effects of C-6 substituents. Structural modifications at the C-1 and C-3 positions led to minimal effects on binding to the digitalis receptor.