Peptidoglycans as promoters of slow-wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination

Abstract

The structures of components of the sleep-promoting material purified from human urine were established by fast atom bombardment-mass spectrometry, as reported in the accompanying paper (Martin, S. A., Karnovsky, M. L., Krueger, J. M., Pappenheimer, J. R., and Biemann, K. (1984) J. Biol. Chem. 259, 12652-12658). We report here that two substances isolated from that preparation, viz. N-acetylglucosaminyl-1,6 -anhydro-N-acetylmuramyl-Ala-gamma-Glu-diaminopimelyl-Ala) and that compound lacking the terminal alanine, are active as somnogens. Cerebro-intraventricular administration of 1 pmol of the glycotetrapeptide was sufficient to induce prolonged excess sleep in rabbits. A similar substance obtained from Brevibacterium divaricatum in which the free carboxyls of the glutamic and diaminopimelic moieties, indicated above, were amidated (N-acetylglucosaminyl-1,6-anhydro-N-anhydromura-myl-Ala-iso- Gln- epsilon-amido-diaminopimelyl -Ala-Ala) was not active as a promoter of slow-wave sleep. Deamidation of this peptide to a mixture of the free dicarboxylic forms produced a somnogenic substance. Our findings show that in addition to the muramyl form of peptidoglycan monomers, the anhydro muramyl form, with no reducing end, is compatible with somnogenic activity. Furthermore, the data obtained with a natural product amplify our earlier observations with smaller synthetic molecules of the importance of amidation/deamidation in the structure-activity relationships of muramyl peptides.