Water Soluble Steroids

It is possible to confer water solubility on pregnane steroids without substantial loss of activity at the GABAA receptor. An example is provided by minaxolone (2^-ethoxy-3a-hydroxy-11a-dimethylamino-5a-pregnan-20-one), studied clinically as a general anesthetic in humans approximately 15 years ago, wherein the incorporation of the 11a-dimethyl amino group results in water solubility (62). Interestingly, in addition to retaining activity at the GABAA receptor (61,63), minaxolone (unlike alphaxalone) acts as a positive allosteric modulator of strychnine-sensitive glycine receptors, albeit with reduced potency vis a vis the effect of the anesthetic on GABAA receptors (64) (see Table 2). Whether this feature can be attributed to only one, or both, of the structural elements (2^-ethoxy and 11a-dimethylamino substituents) that distinguish minaxalone from alphaxalone remains to be determined.

Modulation of GABAA receptor activity by pregnane steroids rendered water soluble by the introduction of a 2^-morpholinyl group has recently been described in detail (22,61) (see Fig. 2). It is clear that the steroid binding site of the GABAA receptor can

Fig. 2. Reduction at C20 decreases the GABA modulatory effects of the pregnane steroids. Top, The chemical structures of six progesterone metabolites tested for GABA-modulatory effects. Bottom, Graphical representation of the relationship between the concentration of bath applied steroid and the current produced by GABA (expressed relative to the current produced by a saturating concentration of GABA). All experiments were performed at a holding potential of -60 mV on Xenopus oocytes expressing human a Py receptors. The steroids investigated were 3a,5a-THPROG, 3a,5p-THPROG, (★); 5a-pregnan-3a,20a-diol, (▲); 5p-pregnan-3a,20a-diol, (H); 5a-pregnan-3a,20p-diol, (#); and 5p-pregnan-3a,20p-diol, (▼). Each point is the mean of data obtained from four to seven oocytes. Vertical lines give the S.E.M.

Fig. 2. Reduction at C20 decreases the GABA modulatory effects of the pregnane steroids. Top, The chemical structures of six progesterone metabolites tested for GABA-modulatory effects. Bottom, Graphical representation of the relationship between the concentration of bath applied steroid and the current produced by GABA (expressed relative to the current produced by a saturating concentration of GABA). All experiments were performed at a holding potential of -60 mV on Xenopus oocytes expressing human a Py receptors. The steroids investigated were 3a,5a-THPROG, 3a,5p-THPROG, (★); 5a-pregnan-3a,20a-diol, (▲); 5p-pregnan-3a,20a-diol, (H); 5a-pregnan-3a,20p-diol, (#); and 5p-pregnan-3a,20p-diol, (▼). Each point is the mean of data obtained from four to seven oocytes. Vertical lines give the S.E.M.

tolerate rather bulky substituents at the 2^-position, because even a 2,6 dibutyl morpholinyl derivative of alphaxalone is accommodated without loss of potency (61). Within a series of 2 p-morpholinyl steroids, 11-keto derivatives are generally more potent allosteric modulators of GABAa receptor activity than their 11-desoxy analogues (61). This accords with previous studies of pregnanes lacking water solubility, where introduction of a keto group at C11 resulted in some loss of activity. The introduction of a hydroxyl moiety at this position, or C12, produces compounds that are essentially inactive (53).

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