Hypoalgesic action of bestatin analogues that inhibit central aminopeptidases, but not neutral endopeptidase.
Two analogues of the aminopeptidase inhibitor bestatin, Z 4212 (N-[(2S, 3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1-oxobutyl]-1- aminocyclopentanecarboxylic) and Z 1796 ((2S)-N-[(2S,3R)-3-Amino-2-hydroxy-4-(4-methylsulphonyl-phenyl)-1- oxobutyl]-L-leucine) were found to behave as hypoalgesics when intracerebroventricularly (i.c.v.) administered to mice in the hot-plate test. At high doses, Z 4212 was also found to reduce the pain threshold after intraventricular (i.v.) administration. Hypoalgesia induced by bestatin analogues was prevented by prior treatment with the opiate receptor blocker naloxone. Thiorphan, a potent inhibitor of NEP, was found to enhance the hypoalgesic effect of low doses of either Z 4212 or Z 1796. These results indicate that both the major opioid-degrading peptidases, i.e. aminopeptidases and neutral endopeptidase (NEP), are individually implicated in the hypoalgesia induced by peptidase inhibitors. In vitro studies showed that these new bestatin analogues readily inhibit aminopeptidases in membranes from mouse c. striatum whereas more than 1000 times the concentration was required for NEP to be blocked. Ex vivo experiments showed that, at variance with bestatin, the hypoalgesic action of Z 4212 or Z 1796 appeared to implicate central aminopeptidases but not NEP, so partially sparing the metabolism of other NEP substrates that might produce additional alterations (substance P and ANP). On the basis of the antitumour and immunomodulatory actions of bestatin, these new analogues might be potentially useful as mixed antitumour and hypoalgesic agents in malignancy.
Otero
M J
MJ
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Iglesias
T
T
Fuentes
J A
JA
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003515:Cycloleucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004744:Enkephalin, Methionine / Q000032:analysis; D007276:Injections, Intraventricular; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010147:Pain Measurement; D011480:Protease Inhibitors / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology
D000700:Analgesics; D011480:Protease Inhibitors; D003515:Cycloleucine; C084579:Z 4212; C084578:Z 1796; D009270:Naloxone; D004744:Enkephalin, Methionine; D015244:Thiorphan; D000626:Aminopeptidases; D015260:Neprilysin; D007930:Leucine; C012211:ubenimex