United States Patent (19) 11 Patent Number: 4,826,824 Schiffman 45) Date of Patent: May 2, 1989

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United States Patent (19) 11 Patent Number: 4,826,824 Schiffman 45) Date of Patent: May 2, 1989 United States Patent (19) 11 Patent Number: 4,826,824 Schiffman 45) Date of Patent: May 2, 1989 (54 METHOD OF ENHANCING THE TASTE 56 References Cited PERCEPTION OF SWEETNESS OF ASPARTAME AND DERVATIVES U.S. PATENT DOCUMENTS THEREOF 3,904,655 9/1975 van den Ouweland et al. ... 549/478 4,399,162 8/1983 Okada ................................. 426/548 (75) Inventor: Susan Schiffman, Durham, N.C. Primary Examiner-Johnnie R. Brown Assistant Examiner-Elli Peselev (73) Assignee: Duke University, Durham, N.C. Attorney, Agent, or Firm-Oblon, Fisher, Spivak, McClelland & Maier Appl. No.: 791,564 (21) (57) ABSTRACT (22) Filed: Oct. 25, 1985 A method for enhancing the ability to perceive the sweetness taste of aspartame or derivatives thereof in (51) Int. Cl.".............................................. A61K 31/70 mammals, which entails exposing all or a portion of the (52) U.S. C. ........................................ 514/47; 514/45; mammalian tongue to an effective amount of a puriner 514/46; 514/48; 426/548 gic nucleotide having at least one phosphate group. 58) Field of Search .................... 426/548; 514/48, 47, 514/45, 46 7 Claims, No Drawings 4,826,824 1. 2 Further, it is an object of the present invention to METHOD OF ENHANCING THE TASTE provide compounds for effecting the described taste PERCEPTION OF SWEETNESS OF ASPARTAME perception enhancement. AND DERVATIVES THEREOF It is also an object of this invention to provide food substances containing the compounds of the present The investigations leading to the present invention invention. were supported by Grant No. NIAAG 00443 from the According to the present invention, the foregoing National Institutes of Health. and other objects are attained by a method for enhanc BACKGROUND OF THE INVENTION ing the ability to perceive the sweetness taste of aspar 10 tame and derivatives thereof in mammals, which entails 1. Field of the Invention exposing all or a portion of the mammalian tongue to an The present invention relates to a method of enhanc effective amount of a purinergic nucleotide having at ing the taste perception of sweetness of aspartame. least one phosphate group. 2. Discussion of the Background Organic compounds, other than carbohydrates, that 15 DETAILED DESCRIPTION OF THE taste sweet have been known for centuries. However, PREFERRED EMBODIMENTS the standard for sweetness has been and remains su Recently, the present inventor adduced data which crose, both in terms of quality of taste and taste profile. suggests that the adenosine receptor, which is known to For example, many compounds reported to be sweet play a significant role in a variety of biological pro have peculiar non-sucrose-like flavors. Moreover, 20 cesses, also appears to play a role in taste perception of sweetness may coexist with other tastes, such as licorice sweeteners. Two subtypes of cell surface adenosine or menthol. Further, some compounds have an unpleas receptors, A1 (inhibitory) and A2 (excitatory) receptors, ant lingering bitter flavor or aftertaste. For example, have been postulated. The A1 types are high affinity both saccharin and cyclamate produce a bitter metallic receptors that show half maximal responses at nanomo aftertaste in practically all tasters at a sufficiently high 25 lar concentrations; while half maximal responses for A2 concentration. Encyclopedia of Chemical Technology, receptors are found at concentrations 100 to 1,000 times Vol. 22, "Sweeteners' (Kirk-Othmer 1980). higher in the micromolar range. The present inventor At present, a satisfactory theory explaining the struc has found that methyl xanthines, including caffeine, ture-activity relationships of compounds perceived to theophylline and theobromine, are potent antagonists of be sweet is lacking. Investigations from a range of disci 30 adenosine receptors. plines, including organic and medicinal chemistry, bio Adaptation of the human tongue to methylxanthines chemistry, neurophysiology, psychophysics and bio having concentrations ranging from 10-M to 102M physics, suggest that there are probably a multiplicity of has recently been shown, by the present inventor, to sweet receptor types each with its own stereochemical potentiate certain tastes. Pharmacol. Biochem. Behay, S. and physicochemical requirements. Hence, if a theory is 35 S. Schiffman et al., 22, 195-203 (1985). Of the five stimuli formulated which is broad enough to encompass di tested, NaCl, quinine HCl, KCl, urea and acesulfam K, verse molecular structures, then many compounds the greatest taste potentiation by methyl xanthines, in which would be predicted to be sweet are not. Alterna fact, approximately 100%, was found for the artificial tively, it is found that if data of a certain series of com sweetener acesulfam K, which had a bitter component pounds can be well accommodated, then structures in addition to sweetness. outside the compound series may not fit the model. To This methylxanthine-enhanced response to sweeten be sure, such theories and correlations lack useful pre ers has been further confirmed, by the present inventor, dictive value. Thus, at present, it is not possible to ratio by electrophysiological data in rats. The animal data, nally design a compound with a molecular structure however, reveals that neural responses in nucleus trac having a predictable sweet taste. Encyclopedia of Chemi 45 tus solitarius for one sweetener, stevilioside, were cal Technology, id. greatly potentiated by 105M caffeine, while sucrose Aspartame has been found to be a suitable substitute was unaffected. Such a result clearly seems to suggest sweetener for a wide variety of foods because of its that the effect of the methyl xanthines is not uniform sucrose-like taste as well as its ability to blend well with acroSS SweetenerS. other food flavors. However, despite its wide spread 50 The present inventor has also demonstrated that use as a substitute sweetener, it is expensive to produce. 10-5M caffeine enhances the taste of some sweeteners Hence, despite the fact that aspartame is being widely including neohesperidin dihydrochalcone, D-trypto used to replace sucrose at present, it would be ex phan, thaumatin, stevioside, and sodium saccharin. tremely desireable to be able to use lesser amounts of Adenosine reversed this potentiation. However, four the sweetener. 55 sweeteners, perhaps some of the more commercially Accordingly, a need continues to exist for a method popular sweeteners, aspartame, sucrose, fructose and whereby the sweetening effects of aspartame and deriv calcium cyclamate, appear to be completely unaffected atives thereof could be attained at a lower concentra by caffeine. tion of the same. However, the present inventor has now discovered that certain purinergic nucleotides enhance the percep SUMMARY OF THE INVENTION tion of sweetness of aspartame, and derivatives thereof Accordingly, it is an object of the present invention but with no measurable effect on other artificial sweet to provide a method of enhancing the sweetness of eners having bitter components such as sodium saccha aspartame and derivatives thereof by enhancing the 11. taste perception of sweetness of aspartame in mammals. 65 Actually, since 1969, it has been known that a 50:50 It is also an object of this invention, particularly, to mixture of 5' disodium inosinate and 5'-disodium guany enhance the taste perception of sweetness of aspartame late has the ability to potentiate the sweetness of a 5% and derivatives thereof in humans. sucrose solution. See Food Technology, Vol. 23, 32-37 4,826,824 3 4. (November 1969). However, no substances have ever ceived intensity of an aspartame concentration pres been known to potentiate the sweetness of aspartame. ented simultaneously with a 10-3M solution of IMP. In accordance with the present invention, it has now Essentially, pieces of chromatography paper (What been discovered that, for example, inosine monophos man No. 1, 0.16-mm thickness) cut in the shape of half phate, inosine diphosphate, inosine triphosphate, guano tongues were soaked in either 103M IMP or deionized sine monophosphate, guanosine diphosphate, guanosine water (control) for 10 minutes. Then, two pieces of triphosphate, adenosine monophosphate, adenosine di chromatography paper, are impregnated with 103 phosphate or adenosine triphosphate potentiate the IMP and a water control, were applied to the tongue for sweetness of aspartame. However, other purinergic 2 minutes. This set was removed and replaced by a fresh nucleotide derivatives may be used. 10 set for another 2 minutes. This constituted a total appli In order to potentiate the sweetness of aspartame in cation time of 4 minutes. accordance with the present invention, the mammalian The aspartame was then delivered to the tongue in tongue or a portion thereof is generally exposed to a inch circles of chromatography paper. A standard con concentration of about 10-6M to 10-M of the puriner centration to be matched was dissolved in 10-3M IMP gic nucleotides of the present invention. However, it is 15 and placed on the side of the tongue adapted to IMP. preferred if the exposure is to a concentration of about The concentration of the test stimulus on the other side 10-4 to 10-2M of the same. was adjusted until a concentration was found that As noted, in accordance with the present invention, matched the intensity of the standard dissolved in IMP. virtually any purinergic nucleotide will potentiate the Using this procedure, a potentiation effect of 40% was sweetness of aspartame and derivatives thereof. This
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