A structure-activity study on the sucrose taste antagonist methyl 4,6-dichloro-4,6-dideoxy-alpha-D-galactopyranoside.

In order to assess the effect of the antagonist methyl 4,6-dichloro-4,6-dideoxy-alpha-D-galactopyranoside (MAD-diCl-Gal) upon the gerbil's chorda tympani sucrose taste response, we tested several concentrations of this compound, as well as single concentrations of closely related derivatives, and found that MAD-diCl-Gal was the most potent inhibitor tested. It appears that the inhibition mechanism is very specific. For example, we have found that 2 chlorine atoms at the C-4 and C-6 positions on the glucopyranoside ring are required for inhibition. In addition, with regard to the orientation of the chlorine atoms, the galacto derivative seems to be more potent than the gluco derivative. We have also found that the methyl glycoside is more potent than the free sugar. With regard to the orientation of the methyl group, MAD-diCl-Gal is more potent than its beta-anomer. (Because of this discovery of the methyl group enhancement and orientation effect, we shall discontinue using the acronym diCl-Gal and replace it with the more specific MAD-diCl-Gal.) Of particular significance is the fact that there appears to be a structure-activity relationship between the most active stimulants and inhibitors in that the requirement for an axial orientation at C-1 and the enhancement by the methyl group at that position are the same in both cases. These results suggest that both the stimulator and the antagonist are acting at the same receptor site.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of the gerbil's sucrose taste response by p-nitrophenyl alpha-D-glucopyranoside and chloramphenicol.

We have discovered that the gerbil's chorda tympani nerve response to sucrose is suppressed by p-nitrophenyl alpha-D-glucopyranoside (PNP-Glu) and chloramphenicol (CAP). Mixture experiments of PNP-Glu and CAP with sodium chloride, potassium chloride, hydrochloric acid, and sucrose gave rise to the following observations: Neither PNP-Glu nor CAP alone stimulates the gerbil's taste nerve; while the sucrose response is suppressed by these inhibitors, taste responses produced by sodium chloride, potassium chloride, and hydrochloric acid are unaffected by the presence of PNP-Glu or CAP; the antagonisms of PNP-Glu and CAP were surmounted by a high concentration of sucrose; CAP is a more potent antagonist (IC50 = 0.0013 M) than PNP-Glu (IC50 = 0.022 M), and both are more potent than methyl 4,6-dichloro-4,6-dideoxy-alpha-D-galactopyranoside (IC50 = 0.048 M); and sucrose antagonism occurs only when PNP-Glu and CAP are mixed with sucrose. It is short-lived and ceases when the mixtures are rinsed from the gerbil's tongue. Structure-activity studies provided the following information: The alpha anomer of PNP-Glu is a more potent inhibitor than its beta anomer; among the PNP-Glu derivatives tested (p-aminophenyl, p-nitrophenyl, and phenyl) only p-nitrophenyl inhibited; among the nitrophenyl galactosides, the para derivative was more potent than the ortho or meta; and p-nitrophenyl alpha-D-mannopyranoside and p-nitrophenyl alpha-D-galactoside are slightly more potent than PNP-Glu. On the basis of concentration experiments, we believe that the inhibitory mechanisms of PNP-Glu and CAP are different, which suggests the existence of at least 2 sucrose receptor sites.