Document Detail

In vitro and in vivo opioid activity of [DPro(6)]dermorphin, a new dermorphin analogue.
MedLine Citation:
PMID:  12732340     Owner:  NLM     Status:  MEDLINE    
To study the effects of inducing stereo-chemical modifications in the structure of dermorphin (DM) so as to improve its mu-opioid receptor affinity and its resistance to C-terminal enzymatic degradation, in the Institute of Molecular Genetics of Moscow, we synthesized a new DM analogue ([DPro(6)]DM) and analyzed the changes induced in the biological activities of DM by substituting the Pro(6) residue with DPro(6). We compared the activity of the new DM analogue and DM in in vitro assays and in in vivo tests of analgesia, thermoregulation, heart rate recordings, and gastrointestinal motility in rats. In the in vitro tests, guinea pig ileum (GPI) and mouse vas deferens (MVD), although the opioid activities of [DPro(6)]DM indicated that the peptide was always less potent than DM, its lower IC(50) ratios (mu/delta) showed that it had higher mu-opioid receptor selectivity. In the in vivo analgesic test, [DPro(6)]DM, when injected intraperitoneally (i.p.) (0.5-5 and 10mg/kg) in rats, had the same antinociceptive efficacy as DM and when injected intranasally (i.n.) (0.005 and 0.02 mg/kg) it induced a more stable and long-lasting analgesia than DM (the AUC was about 91% higher for [DPro(6)]DM than for DM). Moreover, these data confirm that the intranasal route is advantageous for peripheral drug administration. In the heart rate study, [DPro(6)]DM and DM (0.5mg/kg, i.p.), induced a similar, weak bradycardia. The only difference was that [DPro(6)]DM induced a longer-lasting effect than DM. Conversely, in body temperature regulation [DPro(6)]DM induced weaker inhibitory activity than DM (56% of the DM-induced response); it did so only in a cold environment and at the maximal used dose (0.5mg/kg, i.p.) without inducing vasomotor effects. In the gastrointestinal study, [DPro(6)]DM and DM (0.005, 0.05, and 0.5mg/kg, i.p.) significantly slowed upper gastrointestinal transit of a charcoal meal and inhibited colonic propulsion. Comparison of the ED(50) values of [DPro(6)]DM (0.03 mg/kg) and DM (0.009 mg/kg) showed that the DM analogue was about three times less potent than DM in slowing gastrointestinal and colonic transit. In conclusion, all these data overall suggest that structural maneuvering in the Pro(6)-residue of the DM molecule changes its affinity for mu-opioid receptor subtypes and confirms the usefulness of experimental studies involving structural modifications in obtaining new therapeutic agents.
M Broccardo; A B Usenko; M G Uranova; L S Guzevatykh; A A Kamensky; L A Andreeva; L Y Alfeeva; N F Myasoedov; E Giannini; G Improta; T G Emel'yanova
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Peptides     Volume:  24     ISSN:  0196-9781     ISO Abbreviation:  Peptides     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-05-06     Completed Date:  2004-01-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8008690     Medline TA:  Peptides     Country:  United States    
Other Details:
Languages:  eng     Pagination:  419-28     Citation Subset:  IM    
Department of Human Physiology and Pharmacology "V Erspamer," University of Rome "La Sapienza," P le A Moro 5, 00185 Rome, Italy.
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MeSH Terms
Analgesics, Opioid / pharmacology*
Body Temperature Regulation / drug effects
Dose-Response Relationship, Drug
Heart Rate / drug effects
Naloxone / pharmacology
Oligopeptides / pharmacology*
Opioid Peptides
Peristalsis / drug effects
Time Factors
Reg. No./Substance:
0/Analgesics, Opioid; 0/Oligopeptides; 0/Opioid Peptides; 0/dermorphin, (DPro(6))-; 465-65-6/Naloxone; 77614-16-5/dermorphin

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