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

A skin sensitization cross-challenge dataset for a series of alpha-(X-substituted-methyl)-gamma,gamma-dimethyl-gamma-butyrolactones is analyzed in terms of the relative alkylation index (RAI) model. The data analyzed consist of guinea pig sensitization response data for tests in which one lactone derivative is used for the induction stage and then the animals are challenged with another lactone derivative to elicit the response. RAI values 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 alpha-methylene-gamma,gamma-dimethyl-gamma-butyrolactone. Plots of biological response against RAI for induction (RAI(i)) for sets of data in which the same compound is used for challenge have the double-sigmoid shape typical of sensitization response-RAI(i) plots, with some points in the overload region. Relative elicitation potential (REP) values, defined in terms of the biological response when sensitized animals are challenged with the compound in question relative to the response when the same animals are challenged with a chosen reference compound, are obtained. Consistent with the RAI model, plots of REP against RAI(c), the RAI value corresponding to challenge, are linear and the slopes of plots corresponding to different reference compounds are, within the limits of experimental error, in the same ratio as the REP values of the reference compounds. Finally, multiple linear regression 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 coefficients and intercept in this QSAR are similar to those of a QSAR reported previously for sensitization by sulfonate esters. The findings validate the applicability of the RAI model to datasets in which both reactivity 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 haptenation. The similarity between the QSARs for the lactones and for the sulfonate esters suggests that although the two series are very different chemically, the intrinsic antigenicities of the groups transferred to carrier protein are similar.