SYNTHESIS AND INHIBITORY PROPERTIES OF PHEROMONE ANALOGS FOR THE EPOXIDE HYDROLASE OF THE GYPSY-MOTH

A series of analogues of disparlure, the gypsy moth (Lymantria dispar) sex attractant, was synthesized, and the potency of these inhibitors in suppressing the metabolism of disparlure by the L. dispar epoxide h ydrolase (EH) was determined. The analogues substituted at the 6-posit ion (6-hydroxy-, 6-oxo-, and 6,6-difluorodisparlure; (+/-)-threo,cis-1 1, (+/-)-13, and (+/-)-17, respectively), along with 9,9-difluorodispa rlure [(+/-)-26], were the most potent inhibitors (IC50 values of 4-9 mu M). Two other 9-substituted analogues, 9-hydroxydisparlure [(+/-)-t hreo,cis-21] and 9-oxodisparlure [(+/-)-22], were slightly less potent (IC50 values of 18 and 30 mu M, respectively). Analogues substituted at both the 6- and 9-positions (threo,erythro-6,9-dihydroxy-, threo,th reo-6,9-dihydroxy-, and 6,9-dioxodisparlure; (+/-)-threo,erythro-32, ( +/-)-threo,threo-32, and (+/-)-33, respectively) were generally the le ast potent inhibitors (IC50 values of 27-200 mu M). On the basis of a model of the EH active site, a hypothesis is advanced to rationalize t he higher potencies of the 6-substituted analogues. Pheromone metaboli sm plays a key role in pheromone perception, and the potential consequ ences of inhibition of pheromone metabolism are discussed.