title: Synthesis and quantitative structure-activity relationship of 17 beta-(hydrazonomethyl)-5 beta-androstane-3 beta,14 beta-diol derivatives that bind to Na+,K(+)-ATPase receptor.
abstract: A series of 17 beta-(hydrazonomethyl)-5 beta-androstane-3, beta,14 beta-diol derivatives was synthesized and evaluated in the displacement of [3H]ouabain binding from Na+,K(+)-ATPase. The data were explored with multiple linear regression and partial least-squares to find possible quantitatives structure-activity relationships. Good correlations were found between binding to the receptor and van der Waals volumes or molar refractivities of the 17 beta-hydrazonomethyl substituents and pKa values of the compounds. Equivalent results were obtained using the proton affinity (calculated using MOPAC) of the hydrazone residues instead of experimental pKa. As basicity or related electronic factors of the substituents explain a significant portion of the observed changes in the activity, an ion-pair interaction between a carboxylate residue of the enzyme and the protonated 17 beta-hydrazonomethyl group, as postulated by Thomas, plays an important role in the interaction of the ligand to the Na+,K(+)-ATPase receptor.
authors.affiliation: Department of Medicinal Chemistry, Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese (MI), Italy.
authors.forename: L
authors.initials: L
authors.lastname: Quadri
authors.forename: A
authors.initials: A
authors.lastname: Cerri
authors.forename: P
authors.initials: P
authors.lastname: Ferrari
authors.forename: E
authors.initials: E
authors.lastname: Folpini
authors.forename: M
authors.initials: M
authors.lastname: Mabilia
authors.forename: P
authors.initials: P
authors.lastname: Melloni
mesh_terms: D015113:Androstane-3,17-diol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D004285:Dogs; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010042:Ouabain / Q000378:metabolism; D012044:Regression Analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000732:Androstanols; D006835:Hydrazones; D015113:Androstane-3,17-diol; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase