j. Soc. Cosmet. Chem., 47, 363-375 (November/December 1996) Cross-adaptation of sweaty-smelling 3-methyl-2-hexenoic acid by its ethyl esters is determined by structural similarity JOHN D. PIERCE, J•t., DAVID. H. BLANK, EVGUENY V. ARONOV, ZHENRONG GUO, GEORGE PRETI, and CHARLES J. WYSOCKI, Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104-3308 (J.D.P., D.H.B., E.V.A., Z.G., G.P., C..].W.) and Department of Dermatology, School of Medicine (G. P.), and Department of Animal Biology, School of Veterinary Medicine (C..]. W.), University of Pennsylvania, Philadelphia, PA. Accepted jSr publication February 1, 1997. Synopsis Cross-adaptation, the decrease in sensitivity to one odorant after exposure to a different odorant, is affected by perceptual similarity. Recent evidence has shown that structural similarity, in the absence of perceptual similarity, can also influence cross-adaptation. We recently demonstrated cross-adaptation of a 10:1 mixture of (E)- and (Z)-3-methyl-2-hexenoic acid (3M2H), a principal component of human underarm odor, by a 3:1 mixture of the fruity-smelling (E)- and (Z)-ethyl esters of 3M2H (EE3M2H). To further explore the structural basis for this cross-adaptation, we synthesized and purified the individual E- and Z-isomers of EE3M2H and tested them separately for cross-adaptation to a 10E:1Z mixture and a 10Z:1E mixture of 3M2H. The E-isomer of EE3M2H significantly cross-adapted both 3M2H mixtures the Z-isomer of EE3M2H cross-adapted the 10Z:lE mixture only. In threshold tests, the Z-isomer was detected at lower concentrations than were either the E-isomer or a 3E:IZ EE3M2H mixture. These results provide strong evidence that structural similarities underlie the cross-adaptation between 3M2H and its ethyl esters. INTRODUCTION Cross-adaptation, the decrease in sensitivity to one odorant after exposure to a different odorant, has commonly been interpreted as a measure of the degree to which odors share common sensory channels (1-4). Although it has long been known that perceptual similarity influences cross-adaptation, recent evidence has provided insight into how structural similarity, in the absence of perceptual similarity, can also influence cross- adaptation. The present study further investigated the role of structural similarity as it affects cross-adaptation in perceptually distinct compounds: sweaty-smelling 3-methyl- 2-hexenoic acid and its fruity-smelling ethyl ester. Most work in olfactory cross-adaptation from a psychophysical approach has focused on the perceptual relationship between the adapting stimulus and the test stimulus as it determines cross-adaptation. It is now well-established that perceptual analogs, i.e., 363

364 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS compounds with similar odors, but which may have dissimilar chemical structures, cross-adapt (1-5), although the precise relationship between perceptual similarity and cross-adaptation remains obscure. Compounds with similar chemical structures, which have different odors (structural analogs), may also cross-adapt. Cain (6) as well as Cain and Engen (7) have shown cross-adaptation between the structurally similar odorants ,-propanol and ,-pentanol. Engen and Lindstrom (8) reported significant cross-adaptation among a homologous series of aliphatic alcohols that differed in carbon-chain length, although the degree of cross-adaptation did not vary in relation to the degree of physical similarity of the alcohols. More recently, Pierce et •l. (9) demonstrated a significant reduction in the perceived intensity of androstanone (5ot-androstan-3-one) following exposure to an odor- less structural analog, 3-methylidene-5ot-androstane (3MSA). This observation suggests that receptor-level interactions may underlie this phenomenon. We have recently provided further demonstration that structurally similar compounds can cross-adapt (10). The compounds employed were an isomeric mixture of (E)- and (Z)-3-methyl-2-hexenoic acid (3M2H). The E-isomer is a major component (analyti- cally) in male underarm sweat (11,12), which is a biologically and commercially im- portant secretion (13-15). A 10:1 ratio for the E:Z isomers was reported in males (11,12). Axillary extracts from females are qualitatively similar to those from males and also contain E-3M2H however, it is not the major component in females, and the E:Z ratio is different (approximately 16:1) (16). In our previous study, a synthetic mixture of the two 3M2H isomers was formulated in the 10:1 E:Z ratio found in the male secretions (10) and tested for cross-adaptation with three homologous ethyl esters: the ethyl esters of 3-methyl-2-hexenoic acid (EE3M2H), 3-methyl-2-octenoic acid (EE3M20), and 3-methyl-2-pentenoic acid (EE3M2P). The esters, in contrast to the sweaty-smelling organic acids, are pleasant and fruity smelling. Initially, we synthesized and used a purified 3:1 ratio of (E)- to (Z)-ethyl ester isomers for each homologue (10). Each ethyl ester mixture was tested separately for its ability to cross-adapt 3M2H. Significant cross-adaptation between the ethyl esters and 3M2H was noted only for EE3M2H. Following exposure to EE3M2H, 3M2H cross-adapted quickly (estimates were reduced to 65.0% of initial estimates within 30 seconds) and remained cross- adapted for the duration of the adaptation period (overall reduction of 35.1%). Cross- adaptation was asymmetric adaptation to 3M2H did not significantly affect the per- ceived intensity of EE3M2H. Further, there was no significant cross-adaptation noted between 3M2H and the ethyl esters of the lower (EE3M2P) and higher (EE3M20) molecular weight homologues (10). It is unlikely that the differences among the ethyl esters in their efficacy in cross- adapting 3M2H were attributable to perceptual differences. Similarity ratings between the ethyl esters and 3M2H revealed no significant differences among the ethyl esters in their mean similarity rating with 3M2H, i.e., each was rated equally dissimilar to 3M2H (10). A more likely explanation for the pattern of cross-adaptation observed is the greater structural similarity between EE3M2H and 3M2H as revealed by molecular modeling studies (10). Differences in the shape and size of the hydrophobic part of the molecule may determine the extent of cross-adaptation these parameters are identical for