The Efficacy of n-Aliphatic Alcohols and n-Aliphatic Fatty Acids on

5

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The Efficacy of n-Aliphatic Alcohols and n-Aliphatic Fatty Acids on Various Membrane Systems with Special Reference to Olfaction and Taste P. H. PUNTER and B. Ph. M. MENCO State University Utrecht, Psychological Laboratory, Varkenmarkt 2, 3511 BZ Utrecht, The Netherlands H. BOELENS Naarden International, P.O. Box 2, 1400 CA Naarden, The Netherlands

I. Introduction The nature of the receptor-sites responsible for odorous interactions has not yet been elucidated. Some experiments suggest the presence of specific proteinaceous receptors (1,2), whereas other data indicate the involvement of more non-specific lipidic or proteinaceous receptor moieties (3,4,5,6). Homologous series of aliphatic n-alcohols and -fatty acids are useful to test the latter possibility, since numerous studies on membranes involve such compounds (e.g. 7,8). Previous studies using alcohols and fatty acids indicated that olfactory and gustatory thresholds for these compounds are closely related to chemotactic thresholds (4,5). The purpose of the present study is to expand these findings to other membrane-interaction systems, including numerous olfactory and gustatory threshold data supplied by various authors. Moreover, the implications of the present findings will be related to threshold measurements in general. 2. Procedure There are several physico-chemical variables which need to be considered for the present study. These variables have been obtained as described in the following paragraphs. 2.1. Saturated vapor pressures (SVP). All SVP's have been calculated using data given by Dreisbach (9). For both n-aliphatic alcohols and -fatty acids the log SVP is a linear function of the number of carbon atoms (N). For both functions the following regression equations have been obtained: n-aliphatic alcohols:

log SVP=-0.39 N-1.82 log SVP=-0.3T N-1.57 n-aliphatic fatty acids: log SVP=-0.U9 N-2.22 log SVP=-0.U6 N-2.00 in which r is the correlation coefficient and in degrees celsius.

(r=0.99, t=25°) (r=0.99, t=37°) (r=0.99, t=25 ) (r=0.99, t=37°) t the temperature

0097-6156/81/0148-0093$05.00/0 © 1981 American Chemical Society

Moskowitz and Warren; Odor Quality and Chemical Structure ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

94

ODOR QUALITY AND CHEMICAL STRUCTURE

2.2. S o l u b i l i t y data. S o l u b i l i t y data are taken from the l i t e r a t u r e (J_0,J_1_,J_2). S o l u b i l i t i e s can also been c a l c u l a t e d from the octanol/water p a r t i t i o n c o e f f i c i e n t using the method o f Hansch (13) or Yalkowsky and Morozowich (jJO . The f o l l o w i n g r e l a t i o n s h i p s have been found between the l o g s o l u b i l i t y (S) and the number o f carbon atoms (N) f o r the n - a l c o h o l s : 1. B e l l (J2)

l o g S=-0.58 N + 2.30 (t=25-30°)

h. Hansch e t a l .

l

o

f

g

, ^

( t

.

1 5

.

2 5

O

j

C |

_. ) C 8

The c o r r e l a t i o n between l o g S (Mol/l) and the number o f carbon atoms (N) i s l a r g e r than 0.99 i n a l l cases. For the n - f a t t y acids the f o l l o w i n g r e l a t i o n s h i p s have been found between l o g S and the number o f C-atoms: 1. B e l l (_12) l o g S=-0.60 N + 2.32 (t=25-30°) 2. S e i d e l l (JJ_) l o g S=-0.65 N + 3.05 (t=20°, C - C ) 3. Yalkowsky and o Morozowich (_1_U) 6

+

k

9

(

}

0

3

As f o r the n-alcohols the c o r r e l a t i o n between l o g S and the number of carbon atoms i s l a r g e r than 0.99 i n a l l cases. a

2.3. The air/water p a r t i t i o n c o e f f i c i e n t (K /w). The a i r / water p a r t i t i o n c o e f f i c i e n t (K /w) can be c a l c u l a t e d using the f o l l o w i n g formula (j_6) : a

a

K/

w

=

saturated vagor pressure (°K, M o l / l ) . s o l u b i l i t y ( K, Mol/l) i n water

^ ^ ^

Amoore and Buttery (J_T) suggest t o use t h i s formula only i n cases i n which the s o l u b i l i t y i n water at 25°C i s smaller than 10 gram/L For s o l u b i l i t i e s l a r g e r than 10 gram/1 but not i n f i n i t e they propose the f o l l o w i n g equation:

a

K /w

^55.5> k

sol.

;

0.0555

I M+1 P X 0 . 9 T X 1 0

,

(2)

i n which s o l . i s the s o l i b i l i t y i n gram/l, P the SVP i n mm Hg and M the molecular weight. For both n - f a t t y acids and n-alcohols the 25 C values o f the air/water p a r t i t i o n c o e f f i c i e n t s have been c a l c u l a t e d using the s o l u b i l i t y data from ; f o r the 37°C values the s o l u b i l i t i e s given by (j_0) have been used f o r the n-alcohols


5.

95

n-Aliphatic Alcohols and Fatty Acids

PUNTER ET AL.

while f o r the n - f a t t y acids the s o l u b i l i t i e s from (_1_5) have been used. C a l c u l a t i o n o f the l i n e a r r e g r e s s i o n between l o g K /w and the number o f carbon atoms (N) gives the f o l l o w i n g r e s u l t s f o r the n-alcohols: a

at 25°C at 37°C and

a

l o g K /w = -0.195 N + H.17 (r=0.99, C - C ) l o g K /w = -0.306 N + U.31 (r=0.99, C - C )

f o r the n - f a t t y at 25°C at 37°C

3

1 2

3

1 2

a

acids: a

l o g K /w = -O.1U5 N + U.79 (r=0.97, C - C ) l o g K /w = -0.190 N + k.99 (r=0.99, C - C ) 2

9

2

y

a

2.U. Data treatment. L i t e r a t u r e data on the e f f i c a c y o f n-alcohols and n - f a t t y acids i n various model systems, organisms and/or organs have been compiled and compared. The d i f f e r e n t measures o f e f f i c a c y used can be found i n Tables 1 and 2 under p h y s i o l o g i c a l or b i o p h y s i c a l parameter. In the case o f aqueous s o l u t i o n s the l o g - e f f i c a c y was p l o t t e d against the number o f carbon atoms and l i n e a r regressions were c a l c u l a t e d . In the case of gaseous d i l u t i o n s the concentration i n a i r was corrected with the air/water p a r t i t i o n c o e f f i c i e n t t o the concentration i n water and subsequently the l i n e a r r e g r e s s i o n was c a l c u l a t e d . I f the c o r r e l a t i o n between the l o g - e f f i c a c y and the number o f carbon atoms was s i g n i f i c a n t t o at l e a s t 5% the data were used f o r f u r t h e r c a l c u l a t i o n . On basis o f the slopes o f the r e g r e s s i o n l i n e s the chemical p o t e n t i a l (Ay) was c a l c u l a t e d , assuming that the chemicals are i n e q u i l i b r i u m between the membrane and s o l u t i o n phases. The f o l l o w i n g formula has been used (h): Ay(CH °) = a X 2.3 RT 2

C a l

/ m o l e (lcal=0.239 J ) ,

i n which a = the slope o f the r e g r e s s i o n l i n e o f log-concentration versus the number o f C-atoms, R = the gas constant and T = temperature i n °K. 3.

Results

Tables 1 and 2 present the r e l a t i o n s h i p between the l o g e f f i c a c y and number o f carbon atoms o f the n-alcohols and n - f a t t y acids f o r the d i f f e r e n t model systems i n v e s t i g a t e d . For those cases i n which the range o f compounds studied exceeded Cq two r e g r e s s i o n equations were computed. Table 3 presents the Ay values for the n-alcohols. The experiments c i t e d have been c l a s s i f i e d i n four groups: anesthesia, chemotaxis, o l f a c t i o n and t a s t e . The numbers r e f e r t o the data from Table 1. In order t o i n v e s t i g a t e whether there are s i g n i f i c a n t d i f f e r e n c e s between the mean Ay values f o r the four d i f f e r e n t groups t - t e s t s between the means were computed. The r e s u l t s are presented i n Table h. Table 5 presents data analogous t o Table 3 f o r the n - f a t t y a c i d s .


96


Table 1. The Linear Regression Between the Log-Effectiveness (Physiological or Biophysical Parameter) and Number of Carbon Atoms for the n-Aliphatic Alcohols Model systea or

1

2

organise and/or organ

Detection method

Physiological or biophysical parameter

Red blood cell ghost

Uptake

Anesthetic effect

Red blood cells

Hemolysis

Inhibition of 50%

Reference

r**

Range

Slope

Constant

-0.96

C5-C10

-0.60

1.30

(18)

-0.99

C5-C8

-0.40

0.10

-0.99

C1-C10

-0.60

1.04

(18) (19)

-0.99

C1-C8

-0.58

(19)

(19)

3

Lobster axon

Electrophyslology

Anesthetic effect

-0.99

C1-C5

-0.59

0.99 1.37

4

Frog sciatic nerve Squid axon

Electrophyslology

Anesthetic effect

-0.99

C1-C5

-0.43

0.61

(19)

5

Anesthetic effect

-0.96

C2-C8

-0.57

1.49

6

Tadpole

Electrophysiology Reflex

Inhibition

-0.99

C2-C8

-0.56

0.61

(19) (20)

7

Escherichia coli

Negative chemotaxis

Thresholds

-0.86

C1-C4

-1.02

0.11

(21)

8

Physarum polycephalu*

Chemotactic motive force

Thresholds

-0.99

C3-C10

-0.37

-0.56

( I)

b

9

Tetrahynena

Chemotaxis

Thresholds

-0.99

C1-C10

-0.41

-1.02

( _5.)

10

Nitella sp.

Thresholds

-0.99

C3-C8

-0.64

0.87

( I)

11

Human olfactory organ'

Chemotactic electrical response Psychophysical response

Detection threshold

-0.84

C3-C12

-0.39

-2.68

(22)

12

Human olfactory organ

13

Human olfactory organ*

14

15

Human olfactory organ*

Rat olfactory organ

16

Bat olfactory organ*

Psychophysical response Psychophysical rcsoonse

Psychophysical response

Behavioral response

-0.97

C3-C8

-1.52

Detection threshold

-0.99

C3-C8

-0.62 -0.55

(22)

-1.79

(22)

Detection threshold

-0.95

C3-C12

-0.36

-3.07

(23)

-0.96

C3-C8

-0.49

-2.41

(23)

Detection threshold

Detection threshold

C1-C12

-0.28

-1.10

-0.93

C1-C8 C1-C4

-0.42 -0.54

-0.59 0.44

(24) (25)

-0.49 -0.45

0.49

(26)

C2-C10

-4.90

(27)

-0.98 -0.97

C2-C7

-0.55

-4.49

(27)

C1-C8

-0.65

1.76

(28)

-0.94 -0.94 -0.98

C1-C10 C1-C8 C1-C7

-0.65 -0.73 -0.85

1.48 1.78 3.18

(28)


Taste threshold

19

Phornria regina taste hairs Phormia regina

Inhibition proboscis

Rejection threshold taste Rejection threshold taste

Tetanic vibratory response

-0.92

(16) (24)

C2-C8

Human tongue

Gryllus assimilis ovipositor

(16)

-0.48

-0.98 -0.97

Human tongue

21

-0.99

-0.86

Taste threshold

17

Behavioral response

-0.86

C3-C8

-0.95

18

20

C1-C10

Detection threshold

Indirect physiological methods Psychophysical response

tarsal

-0.95 -0.98

Rejection threshold taste

b

*These threshold values have been measured in air and are corrected with the air/water partition coefficient to the concentration in water. ^All r-values are significant at 1*. except for those indicated with b, which are significant at 5%.


(29)



Behavioral

Human o l f a c t o r y


Human o l f a c t o r y organ*

Human o l f a c t o r y organ*


Human tongue

Dog o l f a c t o r y organ

Dog o l f a c t o r y

Phormia r e g i n a , t a r s a l taste h a i r s

25

26

27

28

29

30

31

32

33

response response

-0.87

-0.91

Threshold

- 3 , .06

-0.27 -0.15

C2-C8 C2-C5 -0.87

Threshold

I n h i b i t i o n proscobis

*A11 r-values are s i g n i f i c a n t at 5% except f o r those i n d i c a t e d with a , which are s i g n i f i c a n t at 1%

-0,.36

-10, .25 -0.35 C2-C8 a

-0.83

response

-0.81

- 3 , .29

-0.14

Threshold

C2-C10

- 3 . ,39

- 5 . ,46

-1 .51 - 3 . ,88

-2 .50

-0.36

-0.31

-0.23 -0.19

-0.24

- 1 . ,42

- 3 . 67

- 2 . 12

Constant

Threshold

a

-0.75

Threshold

C2-C9

C2-C9

-0.71

Threshold

Threshold

C1-C10 C2-C9

C1-C10

-0.66 -0.70 -0.70

-0.42

C4-C7

Threshold anosmics

a

-0.17 -0.14

C2-C18

Slope

C3-C7

Threshold normals

-0.99

Threshold

-0.96

Range

Behavioral response


Psychophysical


Psychophysical


Chemotaxis

I n h i b i t i o n 50% Threshold

These threshold values have been measured i n a i r and are corrected with the air/water p a r t i t i o n c o e f f i c i e n t to the concentration i n water.

organ

organ

organ

organ

Nitella

24

Chemotaxis

Anti hemolysis

Human erythrocyte

Physarum Polycephalum

22

23

P h y s i o l o g i c a l or biophysical parameter

organ

Detection method

organism and/or

Model system or

Table 2. The Linear Regression Between the Log-Effectiveness (Physiological or Biophysical Parameter) and the Number of Carbon Atoms for the n-Fatty Acids

(34)

(32) (33)

(27)

(30)

(23) (22)

(31)

(31)

( D

( i)

(19)

Reference


98

Table 3. The Ay values f o r the n - a l i p h a t i c a l c o h o l s f o r four d i f f e r e n t groupings, together with t h e i r means and standard d e v i a t i o n s . The data are taken from Table 1.

ANESTHESIA

X

-536

5-8*

-777

1-8

2

-790

1-5

-576

CHEMOTAXIS

OLFACTION

TASTE

1-4

7

-880 3-8

11

-696

2-8

17

-496

3-10

8

-781

3-8

12

-781

2-7

18

3

-549

3-10

9

-696

3-8

13

-871

1-8

19

1-5

k

-857

3-8

10

-1221

3-8

^k

-987

1-8

20

-764

2-8

5

-563

1-8

15

-1193

1-7

21

-750

2-8

6

-724

1-4

16

-1367

-699

-817

-811

-904

112

404

226

193

Sd. &

Range o f carbon atoms i n the r e g r e s s i o n equation on which the Ay values are based, ftft This number r e f e r s t o the s e r i a l number o f the studies c i t e d i n Table 1. Table k.

t-Tests between the mean Ay values o f the n - a l i p h a t i c a l c o h o l s f o r the four d i f f e r e n t groupings from Table 3.

ANESTHESIA

CHEMOTAXIS

OLFACTION

TASTE

ANESTHESIA n=6 CHEMOTAXIS

t=0.70

n=4

df 8 n.s.

OLFACTION

t=1.09

t=0.03

n=6

d f 10 n.s. t=2.20

df 8 n.s. t=0.43

TASTE n=5

df 9 n.s. n

c

df 7

n

e

n.s.

t=0.73 df 9

n

c

n.s.


5.

n-Aliphatic Alcohols and

PUNTER ET AL.

Fatty Acids

99

Table 5- The Ay values f o r the n - f a t t y acids f o r four d i f f e r e n t groupings together with t h e i r means and standard d e v i a t i o n s . The data are taken from Table 2.

ANESTHESIA

-277

2-18*

22

CHEMOTAXIS

M

-563

OLFACTION

TASTE

4-7

2k

- 2273 7 3 2 - 99

27 21

-199

2-10

30

190 3-7

23

- 3350 5 0 11-10 10 25

-201

2-5

33

327 1- 10 26

X

-277

-376

Sd.

443 1- •9

28

511 2- 9

29

351 2- 8

32

497 2- •8

31

-393

-200

91

ft Range of carbon atoms i n the r e g r e s s i o n equation on which the Ay values are based, ftft This number r e f e r s to the s e r i a l number of the studies c i t e d i n Table 1.

Since the number of experiments used i s smaller than those f o r the n-alcohols i t was not p o s s i b l e to do a s t a t i s t i c a l a n a l y s i s . In Table 6 the mean Ay values and the i n t e r c e p t s of the l i n e a r r e g r e s s i o n l i n e s (from Tables 1 and 2) are compared f o r the n-alcohols and n - f a t t y a c i d s . k.

D i s c u s s i o n and

Conclusion

The n-alcohols and n - f a t t y acids can have d i f f e r e n t e f f e c t s on a v a r i e t y of b i o l o g i c a l functions a s s o c i a t e d with membranes. These e f f e c t s can cause i n h i b i t i o n , s t i m u l a t i o n or b i p h a s i c changes i n membrane bound enzymatic systems (T_)• As can be seen from Tables 1 and 2,the e f f i c a c y of the n-alcohols and n - f a t t y acids i s a l i n e a r f u n c t i o n of chain-length: to o b t a i n the same e f f e c t , a lower concentrations i s needed as the chain-length increases. For the n-alcohols the increase i n e f f i c a c y with i n c r e a s i n g chain-length g e n e r a l l y l e v e l s o f f f o r compounds with more than 8 carbon atoms. This e f f e c t i s seen as a d i f f e r e n c e i n the slope of the r e g r e s s i o n l i n e of the whole range of a l c o h o l s t e s t e d and the slope of the r e g r e s s i o n l i n e up to C 3 . According to Fourcans and J a i n (7_) and J a i n and Wray (J35) the c r u c i a l f a c t o r i n the e f f i c a c y of a l c o h o l s to modify l i p i d


100

ODOR QUALITY AND

CHEMICAL STRUCTURE

Table 6. The mean Ay values and mean i n t e r c e p t s of the r e g r e s s i o n l i n e s of the n - a l i p h a t i c a l c o h o l s and n - f a t t y acids f o r the four d i f f e r e n t groupings and o v e r a l l . The data are taken from Tables 3 and 5.

ANESTHESIA CHEMOTAXIS OLFACTION

Ay

Sd. in _J

o o

TASTE

OVERALL

-699

-817

-811

-904

-802

112

404

226

193

230

INT

0.86

-0.15

-1.06

0.54

0.04

Sd.

0.52

0.82

1.04

2.97

1.68

n

Ay

6

-277

4

6

-376

-393

Sd.

5

21

-200

91

-344 132

Q

^

INT

£

Sd.

-1.80

-2.54

-4.29

-1.83

2.90

-3.41 2.53

h-

< "X

n

1

2

7

2

12

s t r u c t u r e and various f u n c t i o n s (of membranes) i s the hydrop h o b i c i t y of the a l c o h o l . Above a c r i t i c a l chain-length they cause l e s s p e r t u r b a t i o n i n the l i p i d chains between which they are i n t e r c a l a t e d , hence t h e i r e f f i c a c y i s lower. For the n - f a t t y acids i t i s d i f f i c u l t t o f i n d a s i m i l a r e f f e c t ; the reported ranges i n Table 2 are i n most cases too s m a l l . As can be seen from the c o r r e l a t i o n c o e f f i c i e n t s i n Table 2 there i s more s c a t t e r i n the f a t t y a c i d data than i n the a l c o h o l data. The c o r r e l a t i o n c o e f f i c i e n t s are lower i n most cases, although s t i l l significant. The r e s u l t s presented i n Table 1 f o r the n-alcohols are a l l based on i n t e r a c t i o n s with l i p i d - p r o t e i n systems. Results on l i p i d systems only, show a s i m i l a r trend. Table 7 summarizes a number of these s t u d i e s . The Ay value f o r the data from Table 7 i s -858 cal/mole with a standard d e v i a t i o n o f 221. This value i s very s i m i l a r to the o v e r a l l value f o r the l i p i d - p r o t e i n systems (Table 6). In a d d i t i o n , d i s s o c i a t i o n constants based on e l e c t r o - o l f a c t o g r a m s



oil

All

olfactory

tension

Surface tension

Interfacial

measurements

Conductivity

cholestane as probe

r-values are s i g n i f i c a n t at \%

organ

bovine

5. L i p i d monolayers of

system

4. Water-mineral

3. Black l i p i d membrane

phospholipid membranes

2. Human erythrocyte

ESR with 3 - s p i r o -

5°C drop in the

Increase of 1 dyne/cm

Concentration i n aqueous phase to produce i n t e r f a c i a l tension reduction 2 of 1 dyne/cm

Resistance decrease

(B/C r a t i o )

versus m i d f i e l d peaks

Decrease r a t i o low

midpoint t r a n s i t i o n

Concentration for a

Fluorescence with

chlorophyl as a probe

1. D i p a l m i t o y l -

phosphatidylcholine

Detection method

Model system Parameter

-0.99

-0.99

-0.98

C3-C8

C2-C6

C2-C7

C3-C8

C4-C8

-0.99

-0.99

Range

r

Table 7. The Linear Regression Between the Log-Effectiveness and Number of Carbon Atoms for the /i-Aliphatic Alcohols on Different Model Systems

-0.81

-0.85

-0.56

-0.48

-0.55

Slope

0.77

-0.99

1.49

1.53

1.28

(38)

(37)

(20)

(_20)

(36)

Constant Reference

ODOR QUALITY AND

102

CHEMICAL STRUCTURE

for a s e r i e s of n - a l i p h a t i c a l c o h o l s (6_) showed that t h i s parameter i s i n agreement with the f i n d i n g s presented i n Table 1. The Ay values o f the n - a l i p h a t i c a l c o h o l s based on the d i s s o c i a t i o n constants are -1072 cal/mole f o r C t o C and -871 cal/mole f o r C t o C^Q. The c o r r e l a t i o n s between the d i s s o c i a t i o n constant and the number of carbon atoms are -O.96 and -O.9U r e s p e c t i v e l y . The same type of l i n e a r r e l a t i o n s h i p between e f f e c t i v e n e s s and chain-length has been found f o r n-alkanes and n - t h i o l s (39). A d d i t i o n a l support f o r the involvement of phospholipids i n chemoreceptive processes can be deduced from the f a c t that the t h r e s h o l d s f o r c i s - a l i p h a t i c compounds are s i m i l a r or lower than those f o r t r a n s - a l i p h a t i c compounds (U0; own unpublished r e s u l t s ) . This may be due to the f a c t that a l i p h a t i c cis-compounds cause a greater disturbance i n the p h o s p h o l i p i d b i l a y e r than t r a n s - a l i p h a t i c (kj_) compounds. In the case of the n-alcohols the chemical p o t e n t i a l (Ay) appears to be quite s i m i l a r (Table 3) i n the b i o l o g i c a l systems which have been examined here. This suggests that the nature of t h i s p o t e n t i a l i s a c o n s i s t e n t property of membranes found i n d i v e r s e systems measured i n a v a r i e t y of ways. The t - t e s t s over the means for the four groupings (Table k) do not show any s i g n i f i c a n t d i f f e r e n c e s . In the case o f the n - f a t t y acids (Table 5) i t i s more d i f f i c u l t to make a meaningul comparison between the four d i f f e r e n t groupings because of the l i m i t e d amount of data. Comparison of the Ay values and i n t e r c e p t s of the r e g r e s s i o n l i n e s f o r the n-alcohols and n - f a t t y acids (Table 6) shows that the behavior with regard to the e f f e c t i v e n e s s i s r a t h e r independent of the nature of the membrane system. The f o l l o w i n g conclusions can be d e r i v e d from Table 6: 1. From the Ay values i t can be deduced that the t r a n s f e r from the water to the l i p i d phase takes more energy f o r the n-alcohols than f o r the n - f a t t y acids f o r the chain-lengths i n v e s t i g a t e d . 2. From the i n t e r c e p t s i t can be deduced that the s e n s i t i v i t y of the b i o l o g i c a l system i s higher f o r the n - f a t t y acids than f o r the n - a l c o h o l s . In the case o f the n-alcohols the o v e r a l l free energy of adsorption (Ay) i s -800 cal/mole-CH2. This value i s i n agreement with the assumption that the process i s c o n t r o l l e d by hydrophobic i n t e r a c t i o n . According to Seeman (j_9) the hydrophobic region may c o n s i s t of: a. non-polar p o r t i o n s of l i p i d molecules, and/or b. non-polar i n t e r f a c e s between l i p i d and p r o t e i n molecules, and/or c. hydrophobic regions of p r o t e i n molecules. In the case o f the n - f a t t y acids Ay i s c o n s i d e r a b l y lower (Table 6). Since the o i 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 s f o r these compounds are not very d i f f e r e n t from those of the n - a l c o h o l s , i t i s suggested that i n t e r a c t i o n s of p o l a r groups at the i n t e r f a c e of the chemor e c e p t i v e membrane may be r e s p o n s i b l e f o r the d i f f e r e n c e (k). Furthermore d i s s o c i a t i o n e f f e c t s of these acids could p l a y a r o l e . This study p o i n t s to the importance of hydrophobic membrane 3

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regions i n chemoreceptive processes. However, considerably disagreement remains about the a c t u a l r o l e o f these hydrophobic domains. The f o l l o w i n g opinions are quoted from a d i s c u s s i o n i n Hauser (h2): "there i s a c l e a r p o s s i b i l i t y o f phospholipids a c t i n g as a receptor", " i t i s hard to see how the i n t e r a c t i o n o f a drug or a sweet molecule with a phospholipid can r e s u l t i n anything!' and "couldn't i t be p o s s i b l e that the phospholipids play a r o l e i n that they provide the micro-environment o f the p r o t e i n and that the motional state o f the p r o t e i n depends on t h i s environment". This l a t t e r statement i s i n accordance with a conclusion from Fourcans and J a i n (7.) who s t a t e that many d i f f e r e n t membrane bound enzymes or enzyme systems from d i f f e r e n t sources e x h i b i t p a r t i a l or complete dependence upon membrane l i p i d s f o r t h e i r a c t i v i t y . It should be mentioned that data on cockroach antennal (k3) and m a x i l l a r palp (kk) o l f a c t o r y s e n s i l l a show that d i f f e r e n t receptor c e l l s d i s p l a y c o n s i s t e n t l y d i f f e r e n t s e n s i t i v i t i e s towards the same ranges o f n-alcohols (e.g. so c a l l e d pentano and heptanol r e c e p t o r s ) . A d d i t i o n a l l y , the existence o f vertebrate o l f a c t o r y receptor c e l l s which d i s p l a y d i f f e r e n t s e n s i t i v i t i e s for the same a l c o h o l s can be concluded from s i n g l e - u n i t adaptation and cross adaptation studies (k5). Although the e f f e c t s could be due t o d i f f e r e n t p r o t e i n receptor species, they can a l s o be explained on the b a s i s o f d i f f e r e n t l i p i d compositions i n the receptor c e l l s i n question. That rather s p e c i f i c p r o t e i n s are a l s o involved i n chemor e c e p t i v e processes has been shown by s e v e r a l e l e c t r o p h y s i o l o g i c a l ( l ^ A i A 6 » i f l ) and biochemical (U8,j+9,_50) s t u d i e s . Moreover, f r e e z e - f r a c t u r e observations i n d i c a t e the presence o f a high intramembrane p a r t i c l e density i n o l f a c t o r y c i l i a when compared to non-sensory r e s p i r a t o r y c i l i a (5J_,_52 ,_53). Therefore i t i s evident that membranes o f o l f a c t o r y sensory c i l i a d i f f e r from those of non-sensory k i n o c i l i a . Also m i c r o v i l l i from t a s t e receptor c e l l s d i s p l a y high intramembrane p a r t i c l e d e n s i t i e s (_5U). From t h r e s h o l d measurements i t can not be decided whether the hydrophobic domains act as sole receptor s i t e s f o r the substances i n v e s t i g a t e d , though t h i s seems u n l i k e l y considering the above references. I f so, the membranous p a r t i c l e s could represent proteinaceous i o n gates and/ or t r a n s d u c t i n g enzyme systems (e.g. membrane bound nucleotide cyclases) which are a c t i v a t e d by the p e r t u r b a t i o n o f the hydrophobic membrane domains. A l t e r n a t i v e l y these hydrophobic domains could act i n conjunction with more s p e c i f i c proteinaceous receptor s i t e s . In that case at l e a s t part o f the intramembrane p a r t i c l e s represent the a c t u a l receptor s i t e s (53). The studies c i t e d i n t h i s paper show that f o r n - a l i p h a t i c a l c o h o l s (C1-C12) and -acids (C2-C9), o l f a c t i o n and t a s t e act i n s i m i l a r ways as chemotaxis and anesthesia. J a i n et a l . (55.) came to a s i m i l a r conclusion f o r many other membrane systems. Alcohols and f a t t y acids were used i n the present study since o l f a c t o r y and gustatory data on these compounds could be compared with those on many other systems. I t should be kept i n mind that t h r e s h o l d 5


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determinations on other compounds may a l s o only describe nons p e c i f i c i n t e r a c t i o n s . Hence t h r e s h o l d determinations are o f l i m i t e d value f o r answering s p e c i f i c mechanistic questions. However, psychophysical s t u d i e s could c o n t r i b u t e by using compounds with r a t h e r s i m i l a r p h y s i c a l and physico-chemical p r o p e r t i e s . Systematic q u a n t i t a t i v e t h r e s h o l d , s e l f - and c r o s s adaptation measurements using o p t i c a l - , p o s i t i o n a l - , and c i s - t r a n s isomers could provide u s e f u l data. A d d i t i o n a l l y , p r e c i s e assessments o f o l f a c t o r y and gustatory q u a l i t a t i v e sensations may provide more s p e c i f i c answers than q u a n t i t a t i v e assessments (see e.g. 56,57,58)• A combination o f q u a l i t a t i v e and q u a n t i t a t i v e psychophysical experiments on the compounds suggested above could be very u s e f u l e s p e c i a l l y i n combination with e l e c t r o p h y s i o l o g i c a l and biochemical s t u d i e s . L i s t o f abbrevations X = mean values Sd. = standard d e v i a t i o n o f the mean N = number o f studies used n.s. = not s i g n i f i c a n t df = degrees o f Int = i n t e r c e p t

Acknowledgment s This study has been supported by grants from the Netherlands Organization f o r the Advancement o f Pure Research (15-31.06), the N a t i o n a l I n s t i t u t e f o r Water Supply (The Netherlands) and the Centre N a t i o n a l de Recherche S c i e n t i f i q u e ( P a r i s ) . Summary The present study shows that n - a l i p h a t i c a l c o h o l s and f a t t y acids have a s i m i l a r e f f i c a c y f o r o l f a c t i o n and t a s t e as f o r other membrane r e l a t e d d e t e c t i o n systems, e.g. chemotaxis and anesthesia. Using data o f numerous authors,the change i n chemical, p o t e n t i a l per CH -group added f o r the n-alcohols i s -699 cal/mole f o r a n e s t h e s i a , —817 cal/mole f o r chemotaxis, -811 cal/mole f o r o l f a c t i o n , -90U cal/mole f o r t a s t e with an average value o f -802 cal/mole. For the n - a l i p h a t i c f a t t y acids these values are r e s p e c t i v e l y -277 cal/mole, -376 cal/mole, -369 cal/mole, -200 cal/mole and -330 cal/mole. The i n t e r c e p t s ( i n l o g Mol/l) o f the r e g r e s s i o n l i n e s o f the e f f i c a c y versus chain-length f o r the n-alcohols are 0.86 ( a n e s t h e s i a ) , -0.15 (chemotaxis), 1.0U ( o l f a c t i o n ) , 2.97 ( t a s t e ) with an average value o f 1.68. For the n - a l i p h a t i c f a t t y acids these values are r e s p e c t i v e l y -1.80, -2.5*+, -5.07, -1.83 and -3.87. From these data i t has been concluded that i r r e s p e c t i v e o f the membrane system,the t r a n s f e r from the water t o the l i p i d phase takes more energy f o r the n-alcohols than f o r the n - f a t t y acids (chemical p o t e n t i a l values) and that the 2

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i n v e s t i g a t e d membrane-linked systems are more s e n s i t i v e f o r n - f a t t y acids than f o r n-alcohols ( i n t e r c e p t s ) . Suggestions f o r psychophysical experiments which may give more s p e c i f i c answers concerning the mechanisms o f o l f a c t i o n and t a s t e are given.

Literature cited 1. Getchell, M.L. and Gesteland, R.C. The chemistry of olfactory reception: Stimulus specific protection from sulfhydryl reagent inhibition. Proc. Natl. Acad. Sci. USA, 1972, 69, 1494-1498. 2. Menevse, A.; Dodd, G. and Poynder, T.M. A chemical modification approach to the olfactory code. Studies with a thiol-specific reagent. Biochem. J., 1978, 176, 845-854. 3. Cherry, R.J.; Dodd, G. and Chapman, D. Small molecule lipid-membrane interactions and the puncturing theory of olfaction. Biochim. Biophys. Acta, 1970, 211 , 409-416. 4. Ueda, T. and Kobatake, Y. Hydrophobicity of biosurfaces as shown by chemoreceptive thresholds in Tetrahymena, Physarum and Nitella. J. Membrane Biol., 1977, 34, 351-368. 5. Ueda, T. and Kobatake, Y. Changes in membrane potential, zeta potential and chemotaxis of Physarum polycephalum in response to n-alcohols, n-aldehydes and n-fatty acids. Cytobiology, 1977, 16, 16-26. 6. Senf, W.; Menco, B.Ph.M.; Punter, P.H. and Duyvesteyn, P. Determination of odour affinities based on the dose-response relationships of the frog's electro-olfactogram. Experientia, 1980, 36, 213-215. 7. Fourcans, B. and Jain, M.K. Role of phospholipids in transport and enzymic reactions. In: Advances in Lipid Research, 1974, Vol. 12, Paoletti, R. and Kritchevsky, D. (Eds.), Academic Press, New York, pp. 147-226. 8. Hansch, C. and Dunn III, W.J. Linear relationships between lipophilic character and biological activity of drugs. J. Pharm. Sci., 1972, 61 , 1-19. 9. Dreisbach, R.R. Pressure-Volume-Temperature Relationships of Organic Compounds, 1952, Handbook Publ. Inc., 3rd ed., Ohio. 10. Stephen, H. and Stephen, T. Solubilities of Inorganic and Organic Compounds. Vol. 1, Binary Systems, 1963 (1979), Pergamon Press, Oxford. 11. Seidell, A. Solubilities of organic compounds, Vol. II, 1941 , D. van Nostrand Company, New York. 12. Bell, G.H. Solubilities of normal aliphatic acids, alcohols and alkanes in water. Chem. Phys. Lip., 1973, 10, 1-10. 13. Hansch, C.; Quinlan, J.E. and Lawrence, G.L. The linear free-energy relationship between partition coefficients and the aqueous solubility organic liquids. J. Org. Chem., 1968, 33, 347-350. 14. Yalkowsky, S.H. and Morozowich, W. A physical chemical basis for the design of orally active prodrugs. In: Drug Design, 1980, Vol. 9, Ariëns, E.J. (Ed.), Acad. Press, New York, pp. 122-183.


106


15. Ralston, A.W. and Hoerr, C.W. The solubilities of the normal saturated fatty acids. J. Org. Chem., 1942, 7, 546-552. 16. Davies, J.T. and Taylor, F.H. The role of adsorption and molecular morphology in olfaction: The calculation of olfactorythresholds. Biol. Bull., 1959, 117, 222-238. 17. Amoore, J.E. and Buttery, R.G. Partition coefficients and comparative olfactometry. Chem. Sens. Flav., 1978, 3, 57-71. 18. Seeman, P.; Roth, S. and Schneider, H. The membrane concentrations of alcohol anesthetics. Biochim. Biophys. Acta, 1971, 225, 171-184. 19. Seeman, P. The membrane actions of anesthetics and tranquilizers. Pharm. Rev., 1972, 24, 583-655. 20. Paterson, S.J.; Butler, K.W.; Huang, P.; Labell, J.; Smith, I.C.P. and Schneider, H. The effects of alcohols on lipid bilayers: a spin label study. Biochim. Biophys. Acta, 1972, 266, 597-602. 21. Tso, W.W. and Adler, J. Negative chemotaxis in Escherichia coli. J. Bacteriol., 1974, 118, 560-576. 22. Van Gemert, L.J. and Nettenbreijer, A.H. Compilation of odour threshold values in air and water. Central Institute for Nutrition and Food Research, TNO, Zeist, The Netherlands, 1977. 23. Punter, P.H. Measurements of human olfactory thresholds for several groups of structurally related compounds. (in preparation) 24. Moulton, D.G. and Eayrs, J.T. Studies on olfactory acuity II. Relative detectability of n-aliphatic alcohols by the rat. Quart. J. Exp. Psychol., 1960, 12, 99-129. 25. Schmidt, U. Vergleichende Riechschwellenbestimmungen bei neotropischen Chiropteren. Z. Säugetierk., 1975, 40, 269-298. 26. Dethier, V.G. Taste sensitivity to homologous alcohols in oil. Fed. Proc., 1952, 11, 34. 27. Siek, T.J.; Albin, I.A.; Sather, L.A. and Lindsay, R.C, Comparison of flavor thresholds of aliphatic lactones with those of fatty acids, esters, aldehydes, alcohols and ketones. J. Dairy Sci., 1971, 54, 1-4. 28. Dethier, V.G. The limiting mechanism in tarsal chemoreception. J. Gen. Physiol., 1951, 35, 55-65. 29. Dethier, V.G. and Yost, M.T. Olfactory stimulation of blowflies by homologous alcohols. J. Gen. Physiol., 1951, 35, 823-839. 30. Patte, F.; Etcheto, M. and Laffort, P. Selected and standardized values of suprathreshold odour intensities for 110 substances. Chem. Sens. Flav., 1975, 1, 283-307. 31. Amoore, J.E.; Venstrom, D. and Davies, A.R. Measurement of specific anosmia. Percept. Motor Skills, 1968, 26, 134-164. 32. Neuhaus, W. Uber die Riechschärfe des Hundes für Fettsäuren. Z. verg. Physiol., 1953, 35, 527-553. 33. Moulton, D.G.; Ashton, E.H. and Eayrs, J.T. Studies in olfactory acuity IV.Relative detectability of n-aliphatic acids by the dog. Anim. Behav., 1960, 8, 117-128.


5.

PUNTER ET AL.

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Alcohols and Fatty Acids

107

34. Chadwick, L.E. and Dethier, V.G. The relationship between chemical structure and the response of blowflies to tarsal stimulation by aliphatic acids. J. Gen. Physiol., 1947, 30, 255-262. 35. Jain, M.K. and Wray Jr., L.V. Partition coefficients of alkanols in lipid bilayer/water. Biochem. Pharmacol., 1978, 27, 1294-1295. 36. Lee, A.G. Interactions between anesthetics and lipid mixtures. Normal alcohols. Biochemistry, 1976, 15, 2448-2454. 37. Rathnamma, D.V. Mechanism of olfaction explained using interfacial tension measurements. In: Adsorption at Interfaces, Mittal, K.L. (Ed.), 1975, ACS symposium series, Vol. 8, The American Chemical Society, pp. 261-269. 38. Koyama, N. and Kurihara, K. Effect of odorants on lipid monolayers from bovine olfactory epithelium. Nature, 1972, 236, 402-404. 39. Patte, F. and Punter, P.H. Experimental assessment of human olfactory thresholds in air for some thiols and alkanes. Chem. Sens. Flav., 1979, 4, 351-354. 40. Kafka, W.A. Molekulare Wechselwirkungen bei der Erregung einzelner Riechzellen. Z. vergl. Physiol., 1970, 70, 105-143. 41. Pringle, M.J. and Miller, K.W. Structural isomers of tetradecenol discriminate between lipid fluidity and phase transition theories of anesthesia. Biochem. Biophys. Res. Comm., 1978, 192-198. 42. Hauser, H. Phospholipid model membranes: demonstration of a structure-activity relationship. In: Structure Activity Relationships in Chemoreception; Benz, G. (Ed.), IRL London, 1976. pp. 13-24. 43. Sass, H. Zur nervösen Codierung von Geruchsreizen bei: Periplaneta americana. J. comp. Physiol., 1976, 107, 49-65. 44. Altner, H.; Stetter, H. Olfactory input from the maxillary palps in the cockroach as compared with the antennal input. In: Olfaction and Taste, 7, Van der Starre, H. (Ed.), IRL London, 1980. In Press. 45. Baylin, F. and Moulton, D.G. Adaptation and cross-adaptation to odor stimulation of olfactory receptors in the tiger salamander. J. Gen. Physiol., 1979, 74, 37-55. 46. Revial, M.F.; Duchamp, A. and Holley, A. Odour discrimination by frog olfactory receptors: a second study. Chem. Sens. Flav., 1978, 3, 7-23. 47. Caprio, J. Olfaction and taste in the Channel catfish: an electrophysiological study of the response to amino acids and derivatives. J. comp. Physiol., 1978, 123, 357-371. 48. Koshland, D.E. Jr. Bacterial chemotaxis. In: The Bacteria, Vol. 7, Sokatch, J.R. and Ornston, L.N. (Eds.), Acad. Press, New York, 1979. pp. 111-164. 49. Goldberg, S.J.; Turpin, J. and Price, S. Anisole binding protein from olfactory epithelium: evidence for a role in transduction. Chem. Sens. Flav., 1979, 4, 207-215.


108


50. Cagan, R.H. and Zeiger, W.N. Biochemical studies in olfaction: Binding specificity of radioactively labeled stimuli to an isolated olfactory preparation from rainbow trout (Salmo gairdneri). Proc. Natl. Acad. Sci.USA, 1978,75, 4679-4683. 51. Kerjaschki, D. and Hörandner, H. The development of mouse olfactory vesicles and their cell contacts: A freeze-etching study. J. Ultrastruct. Res., 1976, 54, 420-444. 52. Menco, B.Ph.M.; Dodd, G.; Davey, M. and Bannister, L. Presence of membrane particles in freeze-etched bovine olfactory epithelia. Nature, 1976, 263, 597-599. 53. Menco, B.Ph.M. Qualitative and quantitative freeze-fracture studies on olfactory and nasal respiratory epithelia surfaces of frog, ox, rat and dog. II: Cell apices, cilia and microv i l l i . Cell Tissue Res., 1980. In Press. 54. Jahnke, K. and Baur, P. Freeze-fracture study of taste bud pores in the foliate papillae of the rabbit. Cell Tissue Res., 1979, 200, 245-256. 55. Jain, M.K.; Gleeson, J.; Upreti, A. and Upreti, G.C. Intrinsic perturbing ability of alkanols in lipid bilayers. Biochim. Biophys. Acta, 1978, 509, 1-7. 56. Schiffman, S.S. Physicochemical correlates of olfactory quality. Science, 1974, 185, 112-117. 57. Davis, R.G. Olfactory perceptual space models compared by quantitative methods. Chem. Sens. Flav., 1979, 4, 21-35. 58. Boelens, H. and Haring, H.G. Molecular structure and olfactive quality. In: Olfaction and Taste 7, Van der Starre, H. (Ed.), IRL London, 1980. In Press. RECEIVED

November 3, 1980.


The Efficacy of n-Aliphatic Alcohols and n-Aliphatic Fatty Acids on

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