title: Structure-activity relationships of progesterone derivatives that bind to the digitalis receptor: modifications in A and B rings.
abstract: A number of progesterone derivatives, having a 17 alpha-acetoxy group and various functions at C-3 and C-6, interact at the cardiac glycoside (CG) binding site, using [3H]ouabain in a radioligand binding assay (RBA) with membranes from dog myocardium. We now report on results of structure-activity studies concerned with modification of the A and B rings as they influence potency in the RBA. Some progesterone derivatives with 5 alpha- or 5 beta-stereochemistry show weak receptor competing activity. Among the congeners highest potency is associated with the presence of C-4 or C-4,6 unsaturation and a C-6 substituent (CH3, Cl, Br) whose importance appears to reside in its steric rather than electronic character. The C-3 function may be carbonyl, 3 beta-hydroxy or 3 beta-acetoxy when associated with C-4 or C-4,6 unsaturation. In compounds with other substituents that promote activity, C-6 alpha substitution with -CH3, -Cl, or -Br strongly enhances activity; -F, -OCH3, carbonyl, or the unsubstituted compound promotes weak binding; and -OC2H5, -OAc, -OCOOCH3, or -OH eliminates binding activity. Receptor interaction with the double bond at C-4, but not C-5, appears to be particularly important for binding. The most potent analog identified thus far is chlormadinone acetate (17 alpha-acetoxy-6-chloropregna-4,6-diene-3,20-dione), which has 1/20 the potency of ouabain in the RBA. Studies to determine optimal structural requirements for CG-receptor binding by these hormonal steroid congeners, in conjunction with appropriate biological assays, may provide insight into the nature of a putative endogenous counterpart, lead to a better understanding of the mode of action of the CG and yield CG-like compounds with superior therapeutic properties.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Templeton
authors.forename: V P
authors.initials: VP
authors.lastname: Kumar
authors.forename: R S
authors.initials: RS
authors.lastname: Kim
authors.forename: F S
authors.initials: FS
authors.lastname: LaBella
mesh_terms: D000818:Animals; D004071:Digitalis Glycosides / Q000378:metabolism*; D004285:Dogs; D008968:Molecular Conformation; D009206:Myocardium / Q000378:metabolism; D011374:Progesterone / Q000031:analogs & derivatives* / Q000378:metabolism; D011869:Radioligand Assay; D011955:Receptors, Drug / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase; D013329:Structure-Activity Relationship
chemical_list: D004071:Digitalis Glycosides; D011955:Receptors, Drug; C027082:digitalis receptor; D011374:Progesterone; D000254:Sodium-Potassium-Exchanging ATPase