title: Antinociceptive effect of [Met5]enkephalin semicarbazide is not affected by dipeptidyl carboxypeptidase-I.
abstract: Dipeptidyl carboxypeptidase-I is an enzyme involved in the biological degradation of enkephalins. It has been suggested that C-terminal amidation of enkephalins enhances their resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation. In this study, a novel [Met5]enkephalin amide (MEA) analogue [Met5]enkephalin (ME)-semicarbazide synthesized by another laboratory in our group was assessed for its antinociceptive effects compared with ME-ethylamide, MEA and ME, using tail flick test. To protect the administered drugs from biodegradation, rats were pretreated with peptidase inhibitors including amastatin, phosphoramidon and captopril. Then captopril (dipeptidyl carboxypeptidase-I inhibitor) was deleted from the peptidase inhibitors' combination for evaluating in vivo resistance of the synthetic drugs to dipeptidyl carboxypeptidase-I. According to the results, ME-semicarbazide and MEA were resistant enough to dipeptidyl carboxypeptidase-I to exert their strong antinociception following intrathecal administration even in the absence of captopril, whereas the antinociceptive effects produced by ME-ethylamide (10 nmol) were abolished in rats not pretreated with captopril, indicating that significant amounts of the ME-ethylamide were degraded by dipeptidyl carboxypeptidase-I. Replacement of the amide moiety of MEA with semicarbazide provides a new ME derivative, with high analgesic effects as well as more resistance to dipeptidyl carboxypeptidase-I-mediated biodegradation.
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Evin 1983963113, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Rezaee
authors.forename: Seyed Abbas
authors.initials: SA
authors.lastname: Arabanian
authors.forename: Saeed
authors.initials: S
authors.lastname: Balalaie
authors.forename: Abolhassan
authors.initials: A
authors.lastname: Ahmadiani
authors.forename: Leila
authors.initials: L
authors.lastname: Khalaj
authors.forename: Sanaz
authors.initials: S
authors.lastname: Nasoohi
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002216:Captopril / Q000494:pharmacology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004744:Enkephalin, Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology; D006868:Hydrolysis; D007278:Injections, Spinal; D008297:Male; D059225:Nociception / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012663:Semicarbazides / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C572331:(Met5)enkephalin semicarbazide; D000700:Analgesics; D006020:Glycopeptides; D010455:Peptides; D011480:Protease Inhibitors; D012663:Semicarbazides; D004744:Enkephalin, Methionine; C021055:Met-enkephalinamide; C016977:amastatin; D002216:Captopril; D002268:Carboxypeptidases; C008890:phosphoramidon