STEREOSPECIFICITY OF THE SENSORY IRRITATION RECEPTOR FOR NONREACTIVE CHEMICALS ILLUSTRATED BY PINENE ENANTIOMERS

To clarify the existence of a receptor protein for sensory irritants i n trigeminal nerve endings, D- [i.e. (+)] and L- [i.e. (-)] enantiomer s of alpha- and beta-pinene as models of nonreactive chemicals were ev aluated for their potency in outbred OF1 and NIH/S mice using ASTM E98 1-84 bioassay. All pinenes possess sensory irritation properties and a lso induced sedation and signs of anaesthesia but had no pulmonary irr itation effects.. According to the ratio of RD50 (i.e. concentration w hich causes a 50% decrease in respiratory rate, f) and vapour pressure (P degrees), all pinenes are nonreactive chemicals. For nonreactive c hemicals, P degrees and olive oil-gas partition (L-Oil) can be used to estimate their potency as sensory irritant. Thus, for enantiomers wit h identical physicochemical properties, the estimated RD50 values are the same. In addition, although alpha- and beta-pinene do not have ide ntical P degrees and L-Oil values, their estimated potencies are quite close. However, the experimental results showed that D-enantiomers of pinenes were the most potent as sensory irritants and a difference in potency also exists between alpha- and beta-pinene. RD50 for D-enanti omers of alpha- and beta-pinene were almost equal. 1053 ppm and 1279 p pm in OF1 strain and 1107 ppm and 1419 ppm in NIH/S strain, respective ly. Values differed by a factor of similar to 4 to 5 from L-beta-pinen e for which the RD50 was 4663 ppm in OF1 and 5811 ppm in NIH/S mice. R D50 could not be determined for L-alpha-pinene this pinene was almost inactive. D-alpha-pinene seems to best fit the receptor because its ex perimental RD50 was one-half of the estimated value while for D-beta-p inenethose values were equal. On the contrary, L-beta-pinene was about 3 to 4 times less potent than estimated. L-alpha-pinene was only slig htly active although it was estimated to be as potent as D-alpha-pinen e. The remarkable difference in potency between L-enantiometers is mos t likely due to a structural difference between alpha- and beta-pinene : the more flexible beta-pinene fan bend to fit into the receptor bett er than the rigid alpha-pinene. The results showed that the commonly u sed physicochemical descriptors cannot fully explain the potency of th ese chemicals; their three-dimensional structure should also be consid ered. Because of the stereospecificity of pinenes, a target site for n onreactive sensory irritants is most likely a receptor protein contain ing a chiral lipophilic pocket.