Relevance of endogenous 3alpha-reduced neurosteroids to depression and antidepressant action.

The naturally occurring 3alpha-reduced neurosteroids allopregnanolone and its isomer pregnanolone are among the most potent positive allosteric modulators of gamma-aminobutyric acid type A receptors. They play a critical role in the maintenance of physiological GABAergic tone and display a broad spectrum of neuropsychopharmacological properties. We have reviewed existing evidence implicating the relevance of endogenous 3alpha-reduced neuroactive steroids to depression and to the mechanism of action of antidepressants.

Synthesis and biochemical evaluation of some novel benzoic acid based esters as potential inhibitors of oestrone sulphatase.

Oestrone sulphatase is an important target in the fight against hormone-dependent breast cancer. In an effort to investigate the reported definitive pharmacophore for oestrone sulphatase and continue our search for potent inhibitors of this enzyme, we have undertaken extensive synthesis, biochemical evaluation and physicochemical property determination of a range of benzoic acid based esters. Here, we report the initial results of our study into a series of straight chain alkyl esters of 4-sulphonylbenzoic acid.

Evidence for the mechanism of the irreversible inhibition of oestrone sulphatase (ES) by aminosulphonate based compounds.

In our search for the mechanism of the enzyme oestrone sulphatase (ES) we have synthesised and evaluated a number of compounds that were predicted to possess some inhibitory activity. Some of these compounds were indeed found to be inhibitors of ES, whilst other compounds were not. From a consideration of the structure-activity relationship (SAR) of the inhibitors and non-inhibitors of this enzyme, we discovered a factor which we now believe is the main inhibitory moiety within the aminosulphonated inhibitors.

The mechanism of the irreversible inhibition of estrone sulfatase (ES) through the consideration of a range of methane- and amino-sulfonate-based compounds.

We report the results of our study into a series of simple phenyl and alkyl sulfamates and alkyl methanesulfonates as potential inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that the substituted phenyl sulfamates are good irreversible inhibitors; the alkyl sulfamate compounds were found to lack inhibitory activity; whilst the large alkyl chain containing methanesulfonate-based compounds were found to possess weak reversible inhibitory activity. Using the results of the inhibition study, we postulate the probable mechanism for ES and suggest that an attack by the gem-diol is a major requirement prior to the hydrolysis of the sulfamate group, following which, attack on the active site C=O occurs and which therefore leads to the production of an imine type functionality, resulting in irreversible inhibition.

Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer.

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens.