A quantum pharmacological study on diuretics, xanthine, thiazide and triazine derivatives.

The reaction indices of π-electronic structures of the diuretics, xanthine, thiazide and triazine derivatives were calculated. An attempt was made to explain the potency of the diuretic action in the light of quantum chemistry. The reaction indices of xanthine derivatives, the first frontier superdelocalizability at the substi tuent occupying the 7-position of the highest occupied orbital and the second frontier superdelocalizability at the 3-position of the occupied orbital show fairly good cor relations with the diuretic activities. The reaction index Sr”(E) is defined as: S”= fr1/λ1+fr2/λ2, where subscripts 1 nd 2 stand for the highest occupied (or the lowest unoccupied) orbital, and the next highest occupied (or the next lowest unoccupied) orbital, fr is the electron density of the corresponding orbital and λi (i=1, 2) is the coefficient of energy in the i-th molecular orbital ε=α+λ1β, α and beta; being the stand ard Coulomb and resonance integrals. The diuretic activities of thiazide derivatives are in good parallel with the reaction indices, the π-electron densities at the 2-position, at the 4-position and at the 7-position. The potency of carbonic anhydrase inhibi tion of thiazide derivatives and sulphonamide derivatives however are fairly well parallel with the reaction indices, the π-electron density of the lowest unoccupied orbital and the formal charge at the position of amino group or at the position of nitrogen atom in sulphonamide. The diuretic activities of triazine derivatives show good correlation with the reaction indices, the first frontier superdelocalizability of the lowest unoccupied orbital at the 1-position (carbon atom) and the π-electron density of the unoccupied orbital at the 4-position (nitrogen atom). The positions of these diuretics, which are assumed to play the important role in diuretic action, are the positions in the group =N?? -N=. As the values of the Coulomb integral and the resonance integral of trill uoromethyl group (CF3) and the Coulomb integral of carbon atom adjacent to this pseudo-atom, α 2.0β, 1.0β and α-0.1β are employed. Although many studies have been made of the mechanism of action of diuretics, there have been few quantitative studies done on the relation of chemicalphysical characters of diuretics to the potency of the diuretic action. It is difficult to comprehend the potency of the diuretic action from only the chemical configurations of the diuretics. The mechanism of diuretic action of the xanthine derivatives is still uncertain. It has been assumed that the diuresis resulting from the ingestion per os of xanthine diuretics is due to a renal tubular effect (1, 2). For example, aminophylline has been considered to inhibit the enzyme systems in the renal tubule necessary for reabsorption of sodium and chloride with a resultant increase in water excretion. Thiazide derivatives have a common group sulphonamide in the molecule and, ex cept for acetazolamide, have a common heterocyclic (benzothiadiazine) nucleus. Triazine derivatives were suggested as diuretic agents by Lipschitz and Hadidian (3), the general formula of which is as follows: In the mechanism of action of triazine diuretics, a fundamental difference from other diuretic drugs has been assumed (4, 5). These diuretics contain one or more groups =N C-N in the molecule. It has been assumed that this group =N-C-N= is related to diuretic action, however, certain compounds have no diuretic activity in spite of the pre sence of ==N-C-N= . Nachmansohn (6) pointed out that the drug-receptor configuration is quite analogous to the formation of the enzyme-substrate complex. In the interpretation on the substrate specificity for the acetylcholine-esterase, he and his co-workers assumed that the two active sites combine with its substrate molecule. Miledy (7) detected a-bungarotoxin bind ing substances as the ACh-receptors in the neuromuscular junction and materialized the concept of the receptive substance postulated by Langley (8). Beers and Reich (9) asserted that for the nicotinic action of acetylcholine, a distance between the charge of quanternary ammonium group and H-bond between oxygen atom of acetyl group and hydrogen atom of the receptor is necessary to be 5.9 A. This work suggests that a receptor has two ac tive sites. The receptor concept can be applyed to diuretic action. Applying the molecular orbital (MO) method, the present authors attempted calculation of certain reaction in dices (10, 11) of rr-electronic structures for diuretic action of thiazide, xanthine and tria zinc derivatives. Several reaction indices of these diuretics show a fairly good correlation with their diuretic activities, the result of which suggests the presence of two or more ac tive centers in the receptor of the diuretics. The present report is a qualitative explana tion of the action of diuretics in the light of electronic structures. CALCULATIONS Calculated were the following: (A) electronic structures of xanthine derivatives (Fig. 1), thiazide derivatives (Fig. 2), triazine derivatives (Fig. 3) and sulphonamides (Fig. 4) by means of Huckel MO me thod (Molecular Orbital method by simple Linear-Combination of Atomic Orbital). (B) reaction indices of 7r-electronic structures at each position. (C) correlation coefficients between these reaction indices and diuretic activities or the potency of carbonic anhydrase inhibition. Chosed were the reaction indices, in which both the correlation coefficients and rank correlation coefficients were large. The rank correlation coefficient rs is as fol lows: FIG. 1. Structural formulas (rt. side) resulting from xanthine derivatives in quantum chemistry. FIG. 2. Structural formulas of thiazide deriva