Quantitative structure-activity relationships (QSAR) in sweet aspartyl dipeptide methyl esters

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Abstract
In drug design the pharmacochemists frequently use physicochemical constants to correlate the structure with the observed potency. Curiously this approach has hardly been followed by psychophysicists to indicate the increase of taste potency in a series of structurally related compounds of the same stimulus. In the present experiments we correlated the relative sweetness (S) of 40 aspartyl dipeptide methyl esters [general formula CH2(COO−). CH(NH3+ ).CO.NH.CH(R).COOCH3] with 8 physicochemical parameters. Among the compounds we had 7 non-sweet stimuli while the potency of the remaining 33 peptide esters varied from 1 to 27,000 (1 = sucrose). We calculated for the side chain R the values of the parachor parameter P, the hydrophobic fragmental constant f and 5 STERIMOL parameters (L, B1 up to B5). A multiple regression analysis programme selected by stages the most relevant parameters and tested their significance. We observed that the criterion whether a dipeptide ester is sweet or not, is among others defined by the L and B5 parameters of the side chain R. Compounds are sweet provided L is confined to certain limits (0.50 nm5 parameter has to be greater than 0.45 nm (when L0.62 nm). The sweet potency defined as log S correlated very significantly with the parameters P and B4 (n=33, r=0.812, s=0.60, F=29.06). When two compounds, which were shown to be situated at the borderline of the length and volume parameters, were omitted in the analysis, the correlation improved (n=31, r=0.909, s=0.40, F=42.60). In the latter situation we found the following equation when the intercept was set at zero: log S=0.194f + 1.472.10−2P—3.357B5 A previously proposed conformation of aspartame (R=CH2-Ø at the receptor site was computed in detail. We calculated the distances of the AH-B moieties to the third binding site δ (the centre of Ø) and indicated the width of the receptor access for this series of sweet, structurally related, dipeptide methyl esters.

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