novel aspects of structure-activity relationships in sweet taste chemoreception

ELSEVIER

Food Qua& and Prefmcc 5 (1994) 87-93 0 1994 Elsevier Science Limited

Printed in Great Britain. All rights reserved 095&3293/94/$7.00

NOVELASPECTSOFSTRUCTURE-ACTIVITY RELATIONSHIPSINSWEETTASTECHEMORECEPTION

Gordon G. Birch, Roselina Karim & Atala Lopez

Department of Food Science and Technology, University of Reading, Whiteknights, PO Box 226, Reading, UK, RG6 2AP

(Paper pesented at ‘UnderstandingFlavour Quality: Relating Sensory to Chemical and Physical Data ‘, 20-23 September 1992, Bristol, UK)

ABSTRACT

Although sweetness is exhibited by diverse chemical structures, structure-activity relationships within one class have been strictly limited. Across classes the only worthwhile approach has been the search for common AH,B glucophores which seem sufJicient to confer the quality of sweetness. Increased intensity of sweetness demands a degree of lip@hilicity and the more imaginative of the recently proposed models of sweet taste chemorecepion have attempted to relate sweetness to molecular hydrophile- lipophile balance. All of these structure-activity ap- proaches lack predictive power because they fail to take account of the real hydrated state of sweet molecules as they approach and accede to a sweet receptor site.

A modern approach to structure-activity studies rests on the assumption that receptors are normally in a state of interaction with water molecules so that quantitative relationships between molecules must be derived fi-om their aqueous solution pro@rties. By examining the solution properties of defined structures, the effects of chain length and molecular fragments can be individually elucidated. Correlation of solution parameters with time- intensity sensory analyses allows inferences about the real sire of molecules which elicit sweetness. Such data are shown to have a predictive value for both taste quality and sweetness potency.

Keywords: Sweetness; solution properties; structure- activity; molecular volume.

INTRODUCTION

Structure-activity relationships in chemoreception constitute a theme of fundamental and recurrent importance. Soon after its inception in 1970 the Euro- pean Chemoreception Research Organisation held a symposium on the subject (Benz, 1976) and a joint ECRO/SCI symposium on quantitative structure-

activity relationships (QSARs) took place at the Uni- versity of Reading in 1982 (Chem. and Ind., 1983). Beets’ book on human chemoreception (Beets, 1978) probably represents the only true modern monograph on the subject and follows the great pioneering work of Moncrieff (1967).

Molecules seem to be conveniently classifiable into olfactory or gustatory types. The former are of low molecular mass and necessarily volatile. The latter range from about 60 D to over 20 kD. They span widely different chemical classes, even for a single basic taste and they also exist in different shapes, also even for a single basic taste. Some molecules (e.g. chloroform) seem to elicit both taste and smell responses. However, it seems likely that olfactory and gustatory molecules must each (at a stage prior to chemoreception) be soluble in water.

This paper addresses structure-activity relationships in taste and, since the majority of studies have involved sweetness, most of the examples presented relate to sweet molecules.

THE AH,B GLUCOPHORE Shallenberger and Acree (1967) proposed that the necessary structural requirement for sweet taste quality is an AH,B couple in which A and B are each electronegative atoms in suitable geometrical prox- imity. A contains an acidic proton and therefore acts as a hydrogen bond donor whereas B acts as a hydrogen bond acceptor. The AH,B ‘glucophore’, or sweet- eliciting unit, establishes a reciprocal H-bonding system with the AI-LB unit of a receptor. The result is a loose and short-lived association between stimulus molecule and receptor-signalling protein (Birch, 1991 a). The latter then undergoes a conformational change which is subsequently manifested as a cascade of second messenger effects (transduction) involving Gproteins and cyclic AMP (Lancet & Ben-Arie, 1990) in the taste cell.

In the sugars AH,B systems are cu-glycol groups. It seems logical that a sweet molecule should bind with a particular orientation at the taste receptor, which is in

87

88 Gordon G. Birch, Roselina &rim, Atala Lojwz

turn highly stereospecific. For example, cu+mannopyranose is sweet whereas @mannopyranose is bitter (Birch, 1976) and certain u-amino acids are sweet whereas the L-enantiomers are bitter (Solms et al, 1965; Birch & Kemp, 1989; Kemp & Birch, 1992). Attempts have therefore been made to locate the AH,B systems of sweet molecules. However, only in the case of the glucopyranose type of structure, has an exhaustive search been completed. The cr-glycol system at G&C4 appears to be the AH,B group (Birch & Lee, 1974). In most sweet molecules several possible AH,B systems can be noted, but which of these candidates is the effective glucophore is not apparent. Moreover, many molecules possess AH,B systems but are nevertheless not sweet and presumably therefore do not accede to the sweet receptor or are incapable of orientating themselves correctly upon it.

AH,B systems are still thought of as useful guides to the elucidation of sweetness mechanisms (Mathlouthi et al., 1993) but they are evidently insufficient as predictors of sweet taste quality.

INTENSE SWEETNESS AND THE REQUIREMENT FOR LIPOPHILICITY Kier (1972) recognised that intense sweeteners differed from sugars in possessing a lipophilic feature. He claimed that this was a third binding site and proposed extending the Shallenberger and Acree principle so that this became AH,B,y, where y is a hydrophobic centre. It must be emphasised that tripartite attachment is unnecessary for the quality of sweetness because sugars possess little or no hydrophobicity. However, a hydrophobic centre might be anticipated to facilitate an alignment of sapid molecules, and a balance of hydrophilic and lipophilic structural features has recently been correlated with relative sweetness and relative bitterness of molecules (Daniel, 1989).

Whether or not lipophilic or any other molecular features constitute real binding sites on sapid molecules is open to question. On the other hand, there are good reasons to suppose that there are stereospecific regions on the surface of molecules which will define their fit with the sweet or bitter receptors (Rohse & Belitz, 1991). This invokes the concept of shape and size of sapid molecules and leads to valuable inferences about the size of receptors, as well as speculation about multiple points of attachment. It has thus been claimed that the designed chemical synthesis of new sweeteners can be achieved by combining four such putative interaction sites in one molecule (Tinti & Nofre, 1991). This has led to the most potent sweetening agent yet known, sucrononic acid, which is 200000 times sweeter than sucrose.

None of the above theories about glucophores and attachment sites take into account the difference between accession of a sapid molecule to a receptor and its intrinsic activity thereon. One model which does just that has been recorded by Daniel (1989). It is imaginative in that both the accession and the recession of the stimulus molecules are included. However, the published model suffers from arithmetical mistakes and would improve with further refinement.

THE NOVEL APPROACH TO STRUCTURE-ACTIVITY RELATIONSHIPS The novel approach to structure-activity studies lies in consideration of the most important medium for taste receptors, namely water. Receptors probably spend more time interacting with water molecules than with stimulus molecules. Indeed water molecules (as the main components of saliva) help taste cells to maintain their normal state of biological equilibrium. Interac- tion of a taste cell with stimulus molecules represents a disturbance of that equilibrium. In fact, it is arguable that taste cells first respond to changes in water ‘structure’ (caused by dissolved stimulus molecules) rather than to the stimulus molecules themselves and a trend relating detection thresholds of amino acids with their ability to disturb water structure has already been noted (Kemp et al., 1992) (Fig. 1). (This trend is sub stantiated by a linear regression (r = 0.551) , if proline is ignored, justified by its peculiar water-packing properties, r= 0.729)

Water is the only vehicle by which stimulus molecules are transported to the receptor sites and it thus seems logical that those molecules which are most compatible with the water structure should be those which are sub

Threshold values (mM /I)

FIG. 1. The spin-spin relaxation times and threshold values of different L-amino acids.

Structure-Activity Relationshi@ in Sweet Taste Chemoreception 89

sequently conveyed to the deepest layers of the taste epithelium. Water therefore plays a fundamental role in the accession of stimulus molecules. It also plays a role in modifying the shape and size of stimulus molecules, hydrophilic molecules for instance being heavily hydrated upon dissolution. The effective molecular enlargement caused by dissolution is measurable as both hydrostatic and hydrodynamic volumes and might contribute to poor accessibility (slow diffusion) and poor fit with receptors. The novel approach to structure-activity relationships therefore lies in the determination of solution properties as measurements of the effective size, shape and probable functional activities of sapid molecules in a medium of water.

MOLECULAR VOLUMES Molecular volumes can be computed from surface areas and van der Waal’s radii of constituent atoms.

Whilst they are important in the consideration of optimum fit with a receptor, they may bear little resem- blance to the effective volumes of the hydrated structures which are actually presented to the taste receptor. ‘Molecular volumes’ are larger than van der Waal’s volumes because they represent the displace- ment of water molecules by the solute, and water molecules cannot fit into the fine crevices on the surface of the solute molecules, The ‘apparent molecular volumes’ are even larger than the ‘molecular volumes’ and are real measurements of the molecular size in solution (Spillane et al, 1992). They are larger because the solute molecules actually create a void between themselves and the neighbouring solvent molecules. These considerations are of fundamental importance in any field of structure-activity relationships and a recent text (McGowan & Mellors, 1986) is dedicated entirely to the importance of molecular volumes in any form of biological activity. Apparent volumes are usually expressed in molal terms, the ‘apparent molal

-

Polyols Appaa~;~solal

(cm3 / mol)

Apparent specific volumes km3 I g)

CIH20H 101.7 0.668 CH-OH

I HO--C’H

I ~H-OH

c!H~OH

Xylitol

CH,OH

d-OH

HO -C’H

dH-OH

C’H-OH I

CH,OH

Sorbitol

118.0 0.649

Lactitol

202.2 0.587

CH,OH

0.581

FIG. 2. Apparent molal and specific volumes of polyols.

90 Gvrdon G. Birch, Rose&a &rim, Atalu Lopez

TABLE 1. Apparent Specific Volumes (ASV) and Intrinsic Viscosities [q] of Sugars and Polyols (Kemp et al, 1990)

b?l (em3 g-‘) Asv (em3 g-l) b?l/MV

D-Glucose 2.38 0.626 3.80 D-Galactose 2.36 0.607 3.89 BMannose 2.30 0.601 3.83 n-Fructose 2.27 0.616 3.69 n-Xylose 2.30 0.625 3.68 Glucitol 2.41 0.655 3.68 Mannitol 2.47 0.651 3.79 Xylitol 2.37 0.685 3.46 Sucrose 2.41 0.609 3.96 Maltose 244 0.603 4.05 Lactose 2.61 0.614 4.25

volume’ being defined as the apparent increase in volume when 1 mole of solute is dissolved in a large mass of solvent. In terms of hydration, those substances which are most heavily hydrated turn out to have the smallest apparent molal volumes and this is logically explained by their greater interaction with water caus- ing greater electrostrictive forces and collapse of the water structure.

It is sometimes necessary to compare the hydrostatic packing characteristics of two substances which differ in molecular mass. For this purpose it is convenient to divide the apparent molal volume (@V) by the molecular mass to generate the apparent specific volume (ASV) and Fig. 2 shows how these vary in four exemplary permitted sweeteners. Although the sub stances of greater molecular mass have the greatest apparent molal volumes, the opposite occurs for the apparent specific volumes, and this demonstrates that the molecular architectures of the larger molecules allow a more efficent packing arrangement among water molecules. Table 1 compares apparent specific volume (hydrostatic volume) with intrinsic viscosity (hydrodynamic volume). Although the ratio of these two parameters is reasonably constant for the smaller molecules it tends to increase with the disaccharides as the drag effect of the larger molecules becomes evident.

CORRELATIONS OF APPARENT SPECIFIC VOLUMES WITH TASTE QUALITY If solution properties, such as apparent specific volumes, have any value in taste chemoreception for structure-activity relationships, it should be possible to relate them to taste quality. It is then immediately clear that sugars and polyols have closely similar apparent specific volumes (0.60-0.64 cm’g-i for most) which ac- cord with their pure sweet taste (Birch, 1991 b). Intense sweeteners, on the other hand, cover a much broader

TABLE 2

Taste ASV (Cd g-l)

Salty 0.1-0.3 Sour 0.3-0.5 Sweet 0.5-0.7 Bitter 0.7-0.9

range of apparent specific volumes (0.50-0.70 cm’g-‘) which may be the reason for the different qualities of taste which they elicit. This last range probably accounts for most sweet substances and therefore sub stances outside of this range give predominantly different tastes. Indeed, the entire span of human gustatory perception may correspond with the ranges shown in Table 2.

The ranges are to some extent approximate and quantitative; they reflect the packing efficiencies of the different tastant molecules among water molecules. They show, for example, that salt molecules interact very strongly with water molecules. They are heavily hydrated and therefore are presumably conveyed by the water to the deepest layers of the taste epithelium. On the other hand, substances with ASV values above about 0.90 cm3g-’ are beyond the bitter range and therefore tasteless. They are incompatible with the water structure but are probably hydrophobic and possibly volatile. They may therefore generate olfactory responses. Of course, the elicitation of a particular taste quality depends on the possession of an appropriate molecular ‘sapophore’ such as the ‘glucophore’ (men- tioned previously) which is needed for sweetness. Taste quality is therefore ultimately viewed as originating in appropriate solution properties, which determine receptor recruitment, and appropriate sapophores, which determine intrinsic activity at the receptor (Shamil et aZ., 1987). As well as the effective size of the sapid molecule its shape and mode of alignment on the taste receptor are both important. Inferences about both of these can be obtained from solution properties such as apparent specific volume. Indeed fine measurements of the packing characteristics of individual regions of a single molecule can be precisely obtained and they confirm, for example, that the ‘glucophore’ at the 3,4 cr-glycol group of glucopyranosides fits best with water structure (Birch & Shamil, 1988; Shamil et aL, 1989). We can therefore picture sugar molecules as possessing hydration shells with water clustering pref- erentially at one end of the molecule. This constitutes a ‘polarisation’ of the sugar molecule in solution which might well contribute to its alignment on the receptor. We might also conclude from this concept that the water molecules themselves possess a degree of mobil- ity, induced by the sugar, which affects ion-channel behaviour on the taste cell (Mathlouthi & Seuvre, 1988). Apparent specific volumes have been suggested as

Structure-Activity Relationships in Sweet Taste Chemomeption 91

determinants of taste quality differences among the amino acids (Birch & Kemp, 1989) and they may simi- larly account for peptides and other sweeteners tasting different from the sugars. The relationship between apparent specific volume and intrinsic viscosity men- tioned above (Table 1) means that the hydrodynamic volumes are also predictors of the sweetness of sugars and may also prove to be important for the other basic tastes. Finally apparent specific volumes may be com- bined with surface tensions (y) to yield apparent specific parachors (ASV y”) which take account of the different forces of cohesion between the stimulus molecules. They may be regarded as apparent specific volumes if the surface tensions were to remain at unity and have historically been applied with much success by chemists to predict structure-activity relationships in many disciplines (Quayle, 1953; Van der Heijden et al., 1979; Birch & Catsoulis, 1985).

APPARENT SPECIFIC VOLUMES AND TASTE INTENSITY Most structure-taste relationships have been conducted in the field of sweetness and these have centered on the attempted location of glucophores (AH,B systems), hydrophile-lipophile balance, molecular connectivity and size. It is only in recent years that the latter para- meter has been measured by the novel experimental approach of determining apparent volumes in water.

Since low apparent specific volumes are regarded as endowing a molecule with the ability to reach deep receptors they might also be anticipated to elicit greater intensities of response. Moreover, since the persistence of sweet taste is now recognised to be a problem with most of the intense sweeteners, low apparent specific volumes may contribute to greater temporal effects.

If the time-intensity method of analysis is applied to sweeteners it is found that several non-carbohydrate sweeteners elicit larger persistences than do equisweet solutions of sucrose (Noble et cd., 1991). However, this effect may be attributable to differences in the hydrophile-lipophile balance and, in order to make true structure-activity comparisons, it is necessary to examine molecules with similar hydrophilic features.

If the sweeteners listed in Fig 2 are compared by the time-intensity procedure (Table 3), it is clear that those with the lower apparent. specific volumes are both sweeter and more persistent than those with the higher apparent specific volumes when concentrations are expressed on a molar basis. In other words, the larger molecules, which pack more efficiently among water molecules, give the greatest sensory response.

For molecules of different shapes and constitutions it is right to suppose that there is an optimum molecular size to fit the receptor and this approach has been used

TABLE 3. Relationship between Partial Specific Volumes and Intensity and Persistence of Sweetness of Polyols

Polyols Partial specific volumes W3/g)

Intensity” (SW UllitS)b

Persistence (s)

Xylitol

DMannitol

Sorbitol

Maltitol

Lactitol

0.668

0.653 (&

0.649 $9,

0.587 (:.;I,

0.581 (Z4,

34.9 (3.3) 23.8 (2.0) 22.5 (1.6) 56.8 (4.2) 38.1 (3.2)

“Values in parentheses are the standard errors of the means. ’ SMURF, Sensory Measuring Unit for Recording Flux (Birch & Munton, 1981). ’ Intensitv and nersistence of sweetness are reported at 0.3 moljlitre. ’

successfully, for example, structure relationships in McGlinchey, 1981; Spillane et al, 1989). However, for

in examining sweetness- sulphamates (Spillane & & Sheahan, 1989; Spillane molecules such as sugars,

which are structurally all analogous, it is possible that no such size optimum exists.

The best way to explore structure-property relationships is by comparison within an homologous series and this can be done, for example, using glucose syrups, which are abundantly available and common constituents of foods. Glucose syrups are partial starch hydrolysates and are characterised commercially by their ‘dextrose equivalents’ (DE) which are their re- ducing powers (Fehlings solution) calculated as dextrose (n-glucose) and expressed on a dry weight basis. The DE value of a particular glucose syrup can be used to calculate its average chain length or degree of polymerisation (DP) from the relationship, DP = lOO/DE. The apparent molal volumes of glucose syrups of course increase with increasing DP but the apparent specific volumes are found to exhibit the opposite trend (Table 4) and decrease showing better packing characteristics, as the DP increases (Birch & Karim,

TABLE 4. Apparent Specific Volumes and Spin-Spin Relax- ation Times ( T2 Values) of 30% w/w Glucose Syrups Solutions

Dextrose Degree of equivalent polymerisation

(DE) (DP)

12 21

:: 100

8.3 0.6084 0.427 4.8 0.6097 0.538 2.6 O-6112 o-750 1.6 0.6190 0.962 1.0 0.6262 1.139

Apparent specific volumes

@“/mol. wt (a3 g-’ )

T* values 6)

92 Gordon G. Birch, Roselina &rim, Atalu Lqbtz

TABLE 5. Sweetness and Persistence Values of 30% w/v Glucose Syrups Solutions

Dextrose equivalent (DE)

Degree of polymerisation (DP)

Concentration (molar)

hen&y of sweetness Persistence of sweetness (SMURF units) 6)

12 8.3 0.219 15.8 32.8 21 4.8 0.380 22.7 35.6 38 2.6 0.675 41.5 45.7 62 1.6 1.073 52.0 53.7

100 1.0 1.665 63.2 66.2

1992). This means that, as the molecular mass increases, there is a more orderly and efficient hydrostatic packing which can, for example, be related to the NMR pulse relaxation measurements of the solutions. The T2 values, or spin-spin relaxation times of the solutions (also listed in Table 4) show the same trend as the apparent specific volumes and reflect the more ordered state of the larger molecules.

Birch, G. G. (1991 a). Chemical and biochemical mechanisms of sweetness. Food Technol., 45, 114, 116, 119-20.

Birch, G. G. (1991b). Physicochemical properties and applications of sugarless sweeteners. In &gut&: the Way Forward, ed. A. J. Rugg-Gunn. Elsevier Applied Science, London, pp. 18-31.

Birch, G. G. & Catsoulis, S. (1985). Apparent molar volumes of sugars and their significance in sweet taste chemoreception. Chem. Senses, 10,325-32.

It is well known that the sweetness of glucose syrups drops off as the DP increases (i.e. the DE decreases) so that commercial maltodextrins (<20 DE) possess little sweetness. However, O’Donnell (1984) has shown that the taste thresholds of maltooligo-saccharides are very similar and Kearlsey et al. (1980) have published detection thresholds which suggest that the larger molecules may be sweeter than the smaller ones. When the time-intensity sensory analysis procedure is applied to glucose syrups at suprathreshold concentrations, it is found that both intensity and persistence of sweetness increase with increasing DP (Table 5) when expressed on a molar basis. This result is perhaps surprising in view of the slower diffusion of the larger molecules to the taste epithelium, but it accords with the physical properties listed in Table 4 and the results reported above for polyols (Fig 2) and strongly underlines the role of water in the sweetness response.

Birch, G. G. & Karim, R. (1992). Apparent molar volumes and ‘H-NMR relaxation values of glucose syrups.J. Sci. Food Agric., 58,563-g.

Birch, G. G. & Kemp, S. E. (1989). Apparent specific volumes and tastes of amino acids. Chem. Senses, 14,249-58.

Birch, G. G. & Lee, C. K. (1974). Structural functions of taste in the sugar series.J. Food Sci., 39,947-g.

Birch, G. G. & Munton, S. L. (1981). Use of the ‘SMURF’ in taste analysis. Chem. Senses, 6,45-52.

Birch, G. G. & Shamil, S. (1988). Structure, sweetness and solution properties of small carbohydrate molecules. J. Chem. Sot., Farad. Trans. I,, 84, 2635-40.

Chemistry and Industry (1982). Quantitative structure activity relationships (QSAR) in taste and olfaction. 1, 10-44.

Daniel, J. R. (1989). Sweeteners: theory and design. In Frontiers in Carbohydrate Research ed. R. P. Millane, J. N. BeMiller & R. Chandrasekaran. Elsevier Applied Science, London.

Kearsley, M. W., Dziedzic, S. Z., Birch, G. G. & Smith, P. D. (1980). The production and properties of glucose syrups III. Sweetness of glucose syrups and related carbohydrates. Starke, 32,244-7.

CONCLUSIONS This paper outlines a novel approach to structure- activity studies in the field of sweetness which involves the role of water. Solution measurements, when compared to sensory responses, allow inferences about the real size of the stimulus molecules and their mode of interaction with receptors.

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novel aspects of structure-activity relationships in sweet taste chemoreception

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