PubMed · 8287530
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M André, J Valsamis. 1994. Reference values for androstanediol glucuronide.. https://pubmed.ncbi.nlm.nih.gov/8287530/
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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.
We investigated whether 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-androstanediol; 3 alpha-Diol), a neurosteroid whose effects are primarily inhibitory to sexual behavior, may act through interactions with gamma-aminobutyric acid (GABA) receptor complexes (GBRs) in the medial basal hypothalamus (MBH) and the preoptic area (POA). In Experiment (Exp.) 1, ovariectomized (ovx) rats were implanted with bilateral guide cannulae aimed above the MBH and were later treated with 17 beta-estradiol (E2, 2 injections of 1 microgram/0.2 ml in 10% ethanol) and either 3 alpha-Diol (3.0 mg/kg, s.c.) or vehicle. Progesterone (0.5 mg, s.c.) was given 24 h after the first E2 injection and a pre-test for lordosis responsiveness was carried out 4 h later. The GABAA agonist, muscimol (50 ng), then was infused into the MBH and rats were tested 10, 30 and 60 min later. Muscimol infusion facilitated lordosis behavior in vehicle-treated controls, but 3 alpha-Diol-treated animals failed to show this facilitation. To ascertain whether 3 alpha-Diol would also prevent muscimol's action in the POA, a site in which muscimol inhibits, rather than facilitates, sexual receptivity, ovx animals in Exp.2 were implanted with bilateral guide cannulae aimed above the POA and were treated with E2, 3 alpha-Diol, and P and infused and tested as in Exp. 1. Muscimol and 3 alpha-Diol each significantly inhibited receptivity; when they were combined, the inhibition was more pronounced. In Exp. 3, POA infusions of the GABAA antagonist, bicuculline, counteracted muscimol's and 3 alpha-Diol's inhibition of sexual behavior. In Exp. 4, in vitro treatment of POA and MBH membrane fractions with 3 alpha-Diol (30 microM) enhanced maximal [3H]muscimol binding without altering the affinity of the binding sites for the agonist. These data suggest that 3 alpha-Diol inhibits E2 and progestin-induced lordosis behavior via actions at the GBR in both the MBH and POA.