10 The Dependence of Odor Intensity on the Hydrophobic Properties of Molecules Downloaded via YORK UNIV on December 6, 2018 at 04:59:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
MICHAEL J. GREENBERG The Quaker Oats Company, 617 West Main Street, Barrington, IL 60010
The quantitative approach to understanding biological activity depends upon being able to express structure by numerical values and then relating these values to corresponding changes in activity. Relatively little work in this area has been reported on how odor intensity is dependent upon odorant physical chemical properties. Davies and Taylor (1) related threshold to the cross-sectional areas and adsorption constants at an oil-water interface of the odorant molecules. However, these observed and calculated thresholds frequently varied by +1 logarithmic units and sometimes as much as +2.5 units. Guadagni et. al. (2) related molecular weight with the odor threshold values of aliphatic aldehydes in water. Beck (3) assumed that a factor determining an odorant's threshold is its volume, shape, and axis (produced by the odorant's functional group "anchored" at a receptor site) around which the molecule rotates. In another study odor thresholds were related to odorant air water partition coefficients, hydrogen bonding, molecular volume and polarizability by Laffort (4). Laffort et. al. (5) also correlated odor intensity with GLC retention parameters. In still another study Dravnieks (6) correlated 14 structural features with odor threshold and suprathreshold data. More recently Dravnieks (7) correlated odor intensity equivalent to 87 ppm (Vol/vol) of 1-butanol with 20 structural features represented by Wiswesser line notation. The molecular weight term, (log mw) , was reported to be the most statistically significant term. The use of computer techniques in the correlation of biological activity with substrate physical-chemical properties has received much attention in the area of medicinal chemistry. The use of these techniques, denoted Quantitative Structure Activity Relationships (QSAR), were developed mostly by Hansch and his coworkers and have been reviewed by Tute (8), Purcell et. al. (9) and Dunn (10). These techniques were utilized by Greenberg (Ujln the correlation of odor threshold and suprathreshold data with Log P, the log (n-octanol/water partition coefficient). In the same study it was reported that steric and polar effects as measured by the Taft Steric and Polar Constants poorly correlated with odor intensity data. The purpose of this paper is to describe how the Quantitative Structure Activity Relationship (QSAR) technique known as the Hansch O097-6156/81/0148-0177$05.00/0 © 1981 American Chemical Society
Moskowitz and Warren; Odor Quality and Chemical Structure ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
178
ODOR QUALITY AND CHEMICAL STRUCTURE
A p p r o a c h was used in d e r i v i n g m e c h a n i s t i c i n f o r m a t i o n about odor i n t e n s i t y as w e l l as insight i n t o how this b i o l o g i c a l a c t i v i t y m a y be p r e d i c t e d . This paper w i l l f i r s t b r i e f l y d e s c r i b e the h i s t o r y of Q S A R , the Q S A R p a r a m e t e r s used, and how substituents for Q S A R studies are s e l e c t e d . Several e x a m p l e s of t h e H a n s c h A p p r o a c h used i n t a s t e and odor q u a l i t y studies w i l l n e x t be p r e s e n t e d . T h e b a l a n c e of the paper w i l l deal w i t h the d e v e l o p m e n t of q u a n t i t a t i v e s t r u c t u r e odor i n t e n s i t y r e l a t i o n s h i p s w h i c h w i l l f u r t h e r expand upon the e a r l i e r study r e p o r t e d by this author (11). F o r e x a m p l e , the use of r e l a t i v e l y new Q S A R s t e r i c p a r a m e t e r s in c o r r e l a t i o n s w i t h odor i n t e n s i t y d a t a , and c o r r e l a t i o n s of l o g P w i t h l i t e r a t u r e odor i n t e n s i t y d a t a d e t e r m i n e d on a n i m a l panels w i l l be p r e s e n t e d . T h i s w i l l be f o l l o w e d by c o n c l u s i o n s d e r i v e d f r o m those s t u d i e s , and areas of f u t u r e work. H i s t o r i c a l l y one of the f i r s t Q S A R studies was c o n d u c t e d i n 1893 by R i c h e t (12) who c o n c l u d e d t h a t the t o x i c i t y of e t h e r s , a l c o h o l s , aldehydes and ketones was i n v e r s e l y r e l a t e d to t h e i r w a t e r s o l u b i l i t y . In 1899 O v e r t o n (13) and M e y e r (14) c o r r e l a t e d n a r c o t i c a c t i v i t y w i t h l i p i d s o l u b i l i t y ( c h l o r o f o r m - w a t e r p a r t i t i o n c o e f f i c i e n t s ) of a wide v a r i e t y of n o n - i o n i z e d compounds. They found that narcotic a c t i v i t y increased w i t h i n c r e a s i n g l i p o p h i l i c i t y u n t i l l i p i d s o l u b i l i t y b e c a m e so high t h a t the substance was v i r t u a l l y w a t e r i n s o l u b l e . T h e y also found t h a t these compounds p e n e t r a t e d tissue c e l l s as though the m e m b r a n e s were l i p i d i n n a t u r e . T h i s is the f i r s t r e p o r t e d c o r r e l a t i o n b e t w e e n p a r t i t i o n c o e f f i c i e n t s and b i o l o g i c a l a c t i v i t y . A s e c o n d major d e v e l o p m e n t in Q S A R o c c u r r e d in 1939 when F e r g u s o n (15) was a b l e to c a l c u l a t e t o x i c c o n c e n t r a t i o n s of a s e r i e s of compounds f r o m s o l u b i l i t y and vapor pressure d a t a . The next s i g n i f i c a n t advances w e r e m a d e by a t t e m p t s to use s u b s t i t u e n t c o n s t a n t s r a t h e r than p h y s i c a l m e a s u r e m e n t s on the w h o l e m o l e c u l e . In 1940 H a m m e t t (16) d e v e l o p e d the (cr) s u b s t i t u e n t c o n s t a n t s , w h i c h m e a s u r e the degree of e l e c t r o n r e l e a s e / w i t h d r a w a l of a r o m a t i c substituents. B a s e d on the H a m m e t t e q u a t i o n , H a n s e n (17) c o r r e l a t e d b a c t e r i a l g r o w t h i n h i b i t i o n of a s e r i e s of compounds w i t h t h e i r H a m m e t t cr constants. In the e a r l y 1960's H a n s c h and c o w o r k e r s d e v e l o p e d the H a n s c h e q u a t i o n . Since then q u a n t u m m e c h a n i c a l Q S A R and p a t t e r n r e c o g n i t i o n Q S A R have e m e r g e d . T h e H a n s c h a p p r o a c h today is s t i l l a w i d e l y used t e c h n i q u e i n m e d i c i n a l c h e m i s t r y and i n s e c t i c i d e c h e m i s t r y . H i s t o r i c a l l y H a n s c h c o r r e l a t e d the H a m m e t t o~ c o n s t a n t and l o g (no c t a n o l - w a t e r p a r t i t i o n c o e f f i c i e n t ) of p h e n o x y a c e t i c a c i d s w i t h t h e i r plant g r o w t h r e g u l a t o r a c t i v i t y p r o d u c i n g e q u a t i o n 1: 2
L o g A . = -K
{
(log P ) + K A
2
l o g P. + K
3
(1)
In this e q u a t i o n A . ' s represents the a c t i v i t y of the i t h m e m b e r of t h e series s t u d i e d and c a n be in t e r m s of a s t a n d a r d or r e l a t i v e b i o l o g i c a l response. F o r c o m p a r a t i v e purposes A . is usually the r e c i p r o c a l of the m o l a r c o n c e n t r a t i o n r e q u i r e d to e l i c i t a p r e d e t e r m i n e d b i o l o g i c a l response such as E D ^ Q , L D C Q , e t c . T h e t e r m P . is the p a r t i t i o n c o e f f i c i e n t of the c o m p o u n d b e t w e e n fne nonpolar biophase of the b i o l o g i c a l s y s t e m and its aqueous phase, and a c c o u n t s f o r the l i p o p h i l i c c h a r a c t e r of the drug, odorant e t c . 1
Moskowitz and Warren; Odor Quality and Chemical Structure ACS Symposium Series; American Chemical Society: Washington, DC, 1981.
10.
GREENBERG
Odor Intensity and Molecular Hydrophobic Properties
179
The K's are constants determined by regression analysis. A detailed derivation of the equation can be found in a review by Tute (8). If activity is a function of the steric and electronic nature of the compound's substituents, these effects are assumed to be included in the term which can be factored into E and cr , the Taft and Hammett constants or other pertinent linear free energy constants (LFER) as shown in equation 2: K = f(E ,
