Systematic studies on structure and physiological activity of cyclic alpha-keto enamines, a novel class of "cooling" compounds

3-methyl- and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one were recently identified as intense cooling compounds in roasted dark malt. To gain more insights into the molecular requirements of these compounds for imparting a cooling sensation, 26 cyclic alpha -keto enamine derivatives were synthes ized, and their physiological cooling activities were evaluated. Any modifi cation of the amino moiety, the carbocyclic ring size, or incorporation of additional methyl groups led to a significant increase of the cooling thres hold. Insertion of an oxygen atom into the 2-cyclopenten-1-one ring, howeve r, increased the cooling activity, e.g., the cooling threshold of the 5-met hyl-4-(1-pyrrolidinyl)3(2H)-furanone was found to be 16-fold below the thre shold concentration determined for the 3-methyl-2-(1-pyrrolidinyl)-2-cyclop enten-1-one. Shifting the oxygen atom from the 4- into the 5-position of th e cyclopentenone ring resulted in a even more drastic increase in cooling a ctivity, e.g., the 4-methyl-3-(1-pyrrolidinyl)-2(5H)-furanone exhibited the strongest cooling effect at the low oral threshold concentration of 0.02-0 .06 mmol/L, which is 35-fold below the value determined for H-menthol. In c ontrast to the minty smelling (-)-menthol, most of the alpha -keto enamines were found to be virtually odorless but impart a sensation of "cooling" to the oral cavity as well as to the skin, thus illustrating that there is no physiological link between cooling activity and mint-like odors.