Bacterial peptidoglycans as modulators of sleep. I. Anhydro forms of muramyl peptides enhance somnogenic potency.
Chemically defined muramyl peptides (MPs), derived primarily from enzymatic digests of Neisseria gonorrhoeae peptidoglycan, were used to define the structural determinants of MP-mediated somnogenic activity. One of these, i.e. N-acetylglucosaminyl-N-acetyl-1,6-anhydro-N-acetylmuramyl-alanyl-glutamy l- diaminopimelyl-alanine, was structurally identical to the major naturally occurring MP previously detected in mammalian brain and urine. The somnogenic potency of this MP was similar to that of the corresponding disaccharide pentapeptide containing an additional alanine at the C-terminus and the analogous anhydro-muramic acid-containing monosaccharide tetrapeptide lacking the glucosamine moiety. Infusion of as little as 1 pmol of these highly active MPs increased significantly the percentage of slow-wave sleep in experimental animals. In fact, each of 5 anhydro-muramyl disaccharide peptides tested was somnogenic at a dose of 10 pmol or less and, as far as tested, the activity was affected only slightly by the length or composition of the peptide side chain. However, none of a matched set of analogous MPs, differing only in replacement of the anhydro-muramyl end by a hydrated muramic acid residue, was somnogenic at this dose. A modified form of the hydrated muramyl tripeptide containing a free amide on the diaminopimelic acid residue was completely inactive in amounts up to 1000 pmol. Together, the current data suggested: that the anhydro-muramic acid end (but not the glucosamine moiety) is essential for maximal somnogenic potency; and that amidation of carboxyl groups on the peptide-side chain may block MP-mediated somnogenic activity.
D000812:Anhydrides; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009344:Neisseria gonorrhoeae; D010457:Peptidoglycan / Q000494:pharmacology* / Q000652:urine; D011817:Rabbits; D012890:Sleep / Q000187:drug effects*
D000812:Anhydrides; D010457:Peptidoglycan