THE INFLUENCE OF pH ON THE IONIZATION AND BIOLOGICAL ACTIVITY OF d-TUBOCURARINE

¹ Department of Pharmacology, University of Toronto, Canada

1. The dissociation of the two hydroxy groups of d-tubocurarine was investigated. The pK_a values were estimated as 8.1 and 9.1. At and above the physiological pH, d-tubocurarine may be composed of four ionic forms in various proportions which may be presented as ⁺T⁺, ⁺_-T⁺, ⁺T⁺_- and ⁺_-T⁺_-. It was deduced from theoretical considerations that the pK 9.1 can be ascribed with some probability to the OH group of the double ring.

2. The test object for potency determinations of tubocurarine was the isolated frog rectus. The responsiveness of this muscle was influenced by pH. The activity of tubocurarine was therefore assayed in relation to dimethyl-tubocurarine which did not change its ionization at the investigated pH's.

3. The potency of tubocurarine was reduced by an increase of pH. This reduction could be explained on the assumption that most of the activity is associated with the molecule carrying no anionic besides the cationic charges; that the dissociation of the one OH with pK 8.1 causes a great reduction in the activity of the molecule; and that the zwitterion is probably inactive. The influence of the OH group with pK 9.1 could not be determined.

4. When the OH groups were unionized, d-tubocurarine was more potent in the frog rectus than its dimethyl ether. The anionic dissociation of tubocurarine could explain partly, but not completely, the greater potency of dimethyltubocurarine for mammals, as reported in the literature. Possible interpretations of these phenomena were discussed.