Inhibition of Met5-enkephalin-Arg6-Phe7 degradation by inhibitors of dipeptidyl carboxypeptidase.
The heptapeptide Met5-enkephalin-Arg6-Phe7 (YGGFMRF) is cleaved at a high rate by tissue peptidases including dipeptidyl carboxypeptidase. The inhibitor, Hoe 498 diacid (2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo- [3.3.0] octane-3-carboxylic acid), was found to be highly effective in blocking YGGFMRF degradation by a dipeptidyl carboxypeptidase present in a preparation of mouse striatal microsomes. The recovery of YGGFMRF released from rat striatal slices was increased in the presence of Hoe 498 diacid. Furthermore, the recovery of YGGFMRF injected into the caudate was increased in rats pretreated i.p. with Hoe 498 diacid. After i.v. or i.p. injections both Hoe 498 diacid and its prodrug Hoe 498 monoester (2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo [3.3.0] octane-3-carboxylic acid) were detected in rat cerebrospinal fluid and the dipeptidyl carboxypeptidase activity in cerebrospinal fluid was inhibited. These observations indicate that endogenously released YGGFMRF is protected from degradation by Hoe 498 diacid and that systemically administered Hoe 498 diacid or monoester penetrate the blood-brain barrier and inhibit brain and cerebrospinal fluid dipeptidyl carboxypeptidase activity. This potent inhibitor may be useful to block YGGFMRF inactivation in studies of the pharmacology and physiology of YGGFMRF. It is also possible that some of the cerebral effects of these compounds may be referable to an enhancement of YGGFMRF action in the central nervous system.
D000818:Animals; D001812:Blood-Brain Barrier; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D010450:Endopeptidases; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D010539:Permeability; D011480:Protease Inhibitors; D017257:Ramipril; D051381:Rats; D011919:Rats, Inbred Strains
D001643:Bridged Bicyclo Compounds; D011480:Protease Inhibitors; D004744:Enkephalin, Methionine; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D010450:Endopeptidases; C020071:dipeptidyl carboxypeptidase; D017257:Ramipril