title: Synthesis and biological properties of gamma-glutamyl-dermorphin, a prodrug.
abstract: The possibility of using the gamma-glutamyl-transpeptidase system for transformation of inactive propeptide, gamma-glutamyl-neuropeptides into active neuropeptides has been tested on dermorphin and its gamma-glutamyl analogue. Gamma-glutamyl-dermorphin 2 showed little affinity for opioid receptors. Nonetheless, systemic (intraperitoneal (i.p.), or intravenous (i.v.)) application of this compound induced significant antinociceptive effects, although ten to twenty-fold higher doses were required compared to the parent dermorphin 1. On the other hand, the analogue 2 showed high, antinociceptive activity when injected intrathecally (i.t.). When compared to dermorphin, 2 was one third as potent, but did show a significant prolonged duration of the effect. These results suggest that in the periphery, the peptidase metabolism which results in degradation of bioactivity, is offset by gamma-glutamyl-transpeptidase (GGTP) activity that liberates bioactive peptide 2. On the other hand, in the central nervous system, the activity of gamma-glutamyl-transpeptidase system seems to be more effective than other peptidase systems, resulting in formation of active peptide 2 in a significant amount. These data suggests that gamma-glutamyl analogues of neuropeptides can be considered as potential prodrugs, especially for synthetic analogues which themselves are resistant to peptidase action.
authors.affiliation: Department of Chemistry, Warsaw University, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Misicka
authors.forename: I
authors.initials: I
authors.lastname: Maszczynska
authors.forename: A W
authors.initials: AW
authors.lastname: Lipkowski
authors.forename: D
authors.initials: D
authors.lastname: Stropova
authors.forename: H I
authors.initials: HI
authors.lastname: Yamamura
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003164:Competitive Bidding; D008297:Male; D009842:Oligopeptides / Q000378:metabolism*; D018847:Opioid Peptides; D011355:Prodrugs / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; D011355:Prodrugs; C030058:dermorphin