Potassium and magnesium retaining triamterene derivatives.

This work represents a summary of studies carried out with potassium and magnesium retaining triamterene derivatives. The synthesis, analytics and physico-chemical characteristics of those substances are described. Furthermore, the relationships between the chemical structure and electrolyte excretion, pharmacokinetics, metabolism and toxicity are demonstrated. An expanded model regarding the mode of action of triamterene and its derivatives is also presented.

Potassium and magnesium retaining potency and efficacy of triamterene and analogues in conscious saline-loaded rats.

The effect of triamterene and analogues on the acute renal excretion of K+ and Mg2+ was investigated in conscious saline-loaded rats. The maximum retention (Emax) value of the potassium and magnesium retaining efficacy is almost independent of the structure of the compound and depends only on the initial basal value of ion excretion (E0). Triamterene and analogues display a comparable magnesium retaining efficacy. This can be explained by activity against the same renal Mg2+ transportation system. There was a relation between the ED50 values for the potassium and magnesium retaining properties of triamterene derivatives. Both the potassium and the magnesium retaining potency are dependent on the basicity as well as on the lipophilicity of the side chain of the triamterene derivatives. The part of the molecule responsible for the antimagnesiuretic properties of the derivatives seems to be sensitive to steric influences.

Investigations on the acute toxicity of acidic and basic triamterene derivatives.

Acidic and basic triamterene derivatives were evaluated with respect to their acute toxicity. After single intravenous application in mice, derivatives with a basic side-chain were much more toxic than compounds with an acidic side-chain. There is a significant correlation between the potassium retaining properties (measured as ED50) and the acute toxicity (measured as LD50) of the substances. The low acute toxicity after oral application of the compounds can be explained by their low oral bioavailability.

Effects of a new pteridine derivative on urinary sodium, potassium and magnesium excretion in conscious saline-loaded rats.

1. Two recently synthesized pteridine derivatives (RPH 3036; RPH 3038) were tested in conscious saline-loaded rats and showed natriuretic and antimagnesiuretic properties but hardly reduced potassium excretion. 2. In the same model a dose-response curve was performed for RPH 3036. ED50 and Emax values were calculated for the natriuretic (ED50 = 13.4 mumol kg-1; Emax = 1.08 mmol kg-1) and antimagnesiuretic (ED50 = 11.3 mumol kg-1; Emax = -0.099 mmol kg-1) properties of RPH 3036. There were no significant changes of potassium and calcium excretion. 3. After a single dose of RPH 3036 (100 mumol kg-1) the time course of electrolyte excretion was analysed over 6 h. RPH 3036 did not show any significant effects on renal potassium and calcium excretion whereas a pronounced decrease (P less than 0.01) in renal magnesium excretion was evident during the 6 h. A moderate increase of sodium excretion was observed only after 3, 5 and 6 h. 4. A selective reduction of magnesium secretion in the late distal tubule and collecting duct was proposed as a possible mechanism of action of RPH 3036. This would explain the fast onset of action as well as the lack of antikaliuretic and anticalciuretic effects. The high selectivity of RPH 3036 makes it potentially valuable for the future investigation of renal magnesium transport.

Dissociation of the natriuretic and antikaliuretic properties of triamterene derivatives by dose-response experiments.

Several derivatives of triamterene were synthesized with the aim of obtaining physicochemical properties superior to those of triamterene. Their effects on electrolyte excretion were tested with dose-response curves in rats: a dissociation of ED50 values of Na+ excretion from those of K+ retention was found; while the ED50 values of natriuresis were structure independent, the ED50 values for potassium retention depended highly on the charge of the side chain of triamterene derivatives. Acidic compounds displayed low and amines high K+-retaining potencies. Hence we postulate that there are at least two sites of action of the tested compounds in the kidney. (i) The first is the Na+ difference; this is the main driving force for K+ secretion. The affinity to the Na+ conductance is not correlated with the basic/acidic properties of the compounds. (ii) The second site is the finite K+ conductance of the luminal membrane of the distal tubule. The affinity of the drugs to this K+ conductance depends strongly on the charge of the molecule. Only pteridine derivatives with a basic side chain, i.e., with a high pKa value, block the membrane K+ conductance and are therefore potent potassium-retaining drugs.

Pharmacodynamics of straight-chain and branched-chain acidic triamterene derivatives.

The diuretic, natriuretic and antikaliuretic properties of several straight-chain and branched-chain acidic triamterene derivatives were investigated in male Wistar rats. Among the straight-chain compounds the ether of hydroxytriamterene with five C atoms in the side chain (S3) revealed the maximum effects. The iso-compounds (derivatives of 4-carboxymethoxy triamterene S1) showed much better water solubility than the n-acids, but they increased the natriuresis only slightly and had no effect on kaliuresis when they were injected intravenously alone; whereas the isocompound Si4 showed potassium retaining properties when it was administered together with furosemide. From these results it can be suggested that the negative charge in the side chain has to be in a distinct distance from the pteridine ring to produce antikaliuretic effects.

Pharmacodynamics of basic triamterene derivatives.

Triamterene derivatives with a basic side chain and with an additional hydroxyl group in their side chain (hydroxy bases) were investigated for their effects on urine volume and electrolyte excretion in male Wistar rats. All basic derivatives enhance urine volume and sodium excretion. The hydroxy bases show a stronger antikaliuretic effect than the unhydroxylated derivatives. In the group of hydroxy bases the influence of the substitution grade of nitrogen and the role of the pKa values are discussed in order to establish possible structure-activity relationships regarding the antikaliuretic effect.

Pharmacodynamics of acidic triamterene derivatives and their esters and amides.

The diuretic, natriuretic and antikaliuretic effects of two acidic triamterene derivatives, carboxymethoxytriamterene (C2) and carboxybutoxytriamterene (C5), as well as some of their esters and amides were studied in male Wistar rats. The acids and their esters possess similar natriuretic and potassium retaining properties. The esters are nearly completely hydrolyzed to the corresponding acids; therefore, the acids themselves represent the active principle. Compared to the acids and esters the amides have a stronger effect on natriuresis and antikaliuresis. As the amides are excreted partially unhydrolyzed in urine, their pronounced natriuretic and potassium retaining effect must be due to the intact molecule.

Pharmacodynamics and pharmacokinetics of the basic triamterene analogue dimethylaminohydroxypropoxytriamterene.

The diuretic, natriuretic and potassium retaining effects of dimethylaminohydroxypropoxytriamterene (RPH 2823), a basic triamterene derivative, were studied in male Wistar rats. Compared to triamterene (TA) RPH 2823 has a pronounced effect on urine volume and on the excretion of sodium; in addition it possesses a higher antikaliuretic potency than TA. In combination with furosemide, 2.5 mumol/kg RPH 2823 can avoid the kaliuresis of 25 mumol/kg furosemide. The pharmacokinetics of RPH 2823 after i.v. application of 1 mg/kg and 5 mg/kg were studied in female rats. The substance is not metabolized. RPH 2823 has a terminal elimination half-life of 3 h. About 47% of the given dose are excreted unchanged with urine. Furthermore, the volume of distribution VD beta and the total body clearance were calculated.

Studies with triamterene derivatives for oral application.

The diuretic effects, expressed as the urinary Na+/K+ ratios, after oral application of triamterene (TA) and three representatives of a series of TA derivatives - dimethylaminohydroxypropoxytriamterene, carboxybutoxytriamterene and its ethyl ester - are investigated in male Wistar rats. Although the TA analogues are potent diuretics when they are given intravenously, very high oral doses are necessary to produce slight diuretic effects. This result is due to an insufficient absorption of the compounds in the gastrointestinal tract of the rat.

Evidence for an acute antimagnesiuretic effect of triamterene derivatives.

The acute natriuretic, antikaliuretic and antimagnesiuretic effects of two triamterene derivatives, carboxybutoxytriamterene ethyl amide and dimethylaminohydroxypropoxytriamterene (RPH 2823), are shown in male Wistar rats during urine collection periods of 1 to 2.5 h. In combination with furosemide both compounds reduce the potassium excretion that is caused by the loop diuretic. Furthermore, RPH 2823 strongly decreases the magnesiuresis after application of furosemide, and the ethyl amide derivative (25 µmol/kg) reduces the magnesium losses produced by 25 µmol/kg furosemide close to control values. The evaluation of dose-response curves gave further evidence for the hypothesis that the renal handling of K(-) and Mg(2-) is coupled to some extent.