STRUCTURE-ACTIVITY-RELATIONSHIPS FOR CONTACT ALLERGENIC POTENTIAL OF GAMMA,GAMMA-DIMETHYL-GAMMA-BUTYROLACTONE DERIVATIVES .2. QUANTITATIVE STRUCTURE SKIN SENSITIZATION RELATIONSHIPS FOR A-METHYL-GAMMA,GAMMA-DIMETHYL-GAMMA-BUTYROLACTONES

A skin sensitization cross-challenge dataset for a series of -methyl)- gamma,gamma-dimethyl-gamma-butyrolactones is analyzed in terms of the relative alkylation index (RAI) model. The data analyzed consist of gu inea pig sensitization response data for tests in which one lactone de rivative is used for the induction stage and then the animals are chal lenged with another lactone derivative to elicit the response. RAI val ues are based on calculated log P (octanol/water) values together with measured relative rate constants for reactions of the lactones with n -butylamine to form ethylene-gamma,gamma-dimethyl-gamma-butyrolactone. Plots of biological response against RAI for induction (RAI(i)) for s ets of data in which the same compound is used for challenge have the double-sigmoid shape typical of sensitization response-RAI(i) plots, w ith some points in the overload region. Relative elicitation potential (REP) values, defined in terms of the biological response when sensit ized animals are challenged with the compound in question relative to the response when the same animals are challenged with a chosen refere nce compound, are obtained. Consistent with the RAI model, plots of RE P against RAI(c), the RAI value corresponding to challenge, are linear and the slopes of plots corresponding to different reference compound s are, within the limits of experimental error, in the same ratio as t he REP values of the reference compounds. Finally, multiple linear reg ression analysis gives a quantitative structure-activity relationship (QSAR) covering the complete set of cross-challenge data, relating the biological responses to the RAI(i) and RAI(c) values. The coefficient s and intercept in this QSAR are similar to those of a QSAR reported p reviously for sensitization by sulfonate esters. The findings validate the applicability of the RAI model to datasets in which both reactivi ty and lipophilicity are varied and support the argument that for the lactones studied the elimination reaction with n-butylamine is a good model for the rate-determining step of in vivo carrier protein haptena tion. The similarity between the QSARs for the lactones and for the su lfonate esters suggests that although the two series are very differen t chemically, the intrinsic antigenicities of the groups transferred t o carrier protein are similar.