Bis-quaternary Ammonium Compounds Research Articles

Ethiquinium chloride, an asymmetric bisquaternary ammonium salt, in the therapy of hypertension.

EXPERIENCE accumulated with the use of hypotensive agents over the past decade has suggested that prolonged, meticulous pharmacotherapy may be associated with an alteration in the basic process causing hypertension.1 These data have prompted the conviction that every patient with documented high blood pressure should be offered a trial of therapy.2 "Chemical sympathectomy" with hexamethonium and pentolinium derivatives has attracted particular attention among the various modalities of treatment. Structurally, these compounds are symmetric bisquaternary ammonium salts, and their efficacy led to the exploration of possible vasodepressor properties of the closely related asymmetric bisquaternary ammonium compounds, of which chlorisondamine3 is the . . .

Curare-Like Activity of Some Bis-Fluorenyl-Bis-Quaternary Ammonium Compounds

1. The curariform activity of a new series of bis-quaternary ammonium compounds is reported. 2. Moderate increase of activity is obtained by shortening the distance between nitrogen atoms from approximately 15 Å to 9 Å. 3. Replacement of N-ethyl groups with N-methyl in the 6-carbon chain analog decreases both the activity and the subcutaneous absorption in mice, but has no effect on the activity as measured in dogs and rabbits.

Equidistance concept and structure-activity relationship of curarizing drugs.

1. In a selection of representatives of the four major types of bisquaternary ammonium compounds selectively interfering with neuromuscular transmission and of some congeners lacking such selectivity, the linear intramolecular distance between the two reactive onium nitrogens was measured in molecular models. 2. The reactive atom distance was found to be variable over a wide range in each individual compound, multiple rotation about atomic bonds along the N-to-N interjacence allowing variation of the spatial arrangement of the molecule. 3. From no aspect, including the assumption that the maximum N-to-N distance is prevalent because of the mutual repulsion of the cationic heads, was it possible to find any correlation between selective activity and the reactive atom distance. 4. These observations and a discussion of other pertinent data were employed to evaluate the hypothesis that the N-to-N interjacence of bis-onium compounds serves as a rigid spacer of the cationic heads and that curarizing activity is explained by the reaction of optimally spaced onium groups of the drug with equidistant co-reactive groups of a biological receptor substance (equidistance hypothesis of curarizing activity). It is concluded that the equidistance hypothesis in its present form cannot be reconciled with the facts known about any of the various types of drug interference with neuromuscular transmission and the prominent representatives of these activities. 5. In order to demonstrate that with no lesser ease diametrically opposite concepts can be formed, in which the emphasis is shifted from the mere spacer role of the interjacence to the details of the spatial arrangement of the interjacence, an example is presented of the application of an “adumbration” hypothesis of curarizing activity to the series of bis-onium polymethylenes; in contrast to the equidistance hypothesis, this hypothesis applies to non-bis-onium compounds as well as to bis-oniums. 6. The adumbration hypothesis, though by no means offered as an explanation of curarizing activity, is found useful to accentuate the necessity of a return to considerations of the totality of tectonic and bonding potentialities whihc determine the spatial and energetic fit between drug and receptor.