Diuretics structure-activity relations

Potentiometric 30% EtOH in Novello FC and Sprague JM, Structure-activity relations among the H2O thiazide diuretics,Chim. 32 (Special no.), 222-225 (1967). 

Alternatively, sodium entry through the luninal faces of the cells of the distal tubule may be blocked. Specific blockade of these channels by diuretic substances are now considered with particular reference to their structure—activity relations and mechanisms of action. The following classes of substances have been shown to have blocking activity at these sites fV-amidinopyrazine carboxamides, aminopteridines, aminopyrimidines, triazines, and azidopyrimidines, the first two of these groups being the most important. 

These, then, are the major deficiencies to be filled by the design of new diuretics, and they constitute the immediate objectives of many medicinal chemists working in the area of renal drugs. The following discussion concerns some selected aspects of our own work that has been directed to the search for compounds to fill these deficiencies. This discussion will deal with three categories of compounds (1) compounds designed to mimic the mercurials, (2) the sulfonamides, particularly the hydrothiazides and (5) a heterocyclic class of potassium-sparing diuretics. A complete or detailed analysis of structure-activity relations will not be presented these either have been or will be published. Emphasis is placed on the inception of these compounds and on certain points related... 

This summary of our results brings us to the question What is the evidence that the diuretic activity of these mercury-free structures is related to the reaction with a sulfhydryl system or related nucleophilic system The evidence is mostly circumstantial and must be drawn largely from the extensive studies with ethacrynic acid. 

The thiazide diuretics possess antihypertensive properties, in part consequent upon electrolyte and plasma-volume changes but mainly resulting from a direct cardiovascular depressant effect. This is clearly illustrated by the non-diuretic thiazide, diazoxide, which is an effective hypotensive [326b, c]. It is not therefore, surprising that both these properties should be found (in varying proportions) in other, structurally related, compounds. One particular line of research, aimed at modification of the thiazide heterocycle (the o-chlorobenzenesulphonamide moiety was untouched as it was believed essential to activity-the subsequent advent of ethacrynic acid questions this belieO examined first the corresponding... 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

Theobromine (3,7-dimethylxanthine, 3,7-dihydro-3,7-dimethyl-lW-purine-2,6-dione). C7H,N402, Mr 180.17 formula, see under theophylline. Monoclinic, bitter tasting needles, mp. 357 °C, sublimes at 290-295 °C, soluble in hot water, alkali hydroxides, concentrated acids, moderately soluble in ammonia, poorly soluble in cold water and alcohol. With acids T. forms salts which decompose in water detection by the murexid reaction. T. is the main alkaloid of cocoa (Theobroma cacao, 1.5-3 wt.-%), from which it is obtained - especially from the husks in which it accumulates during fermentation. The typical bitter taste of cocoa is the result of interactions between T. and the pip-erazinediones formed in the roasting process. T. has diuretic, vasodilatory, and stimulating effects on cardiac muscle. The activities are weaker than those of the structurally related caffeine (a methylation product of T.) with which it co-occurs in cola nuts. For further pharmacological properties, see table under theophylline. 

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