Abstract
Recent evidence suggests that highly selective μ-opioid agonists may provide good analgesia with less development of tolerance and dependence. H-Tyr-d-Arg-Phe-Lys-NH2 (DALDA) and H-Dmt-d-Arg-Phe-Lys-NH2([Dmt1]DALDA) were found to display high binding affinity and much greater selectivity for the μ-opioid receptor (Kiδ/Kiμ> 10,000) compared with H-Tyr-d-Ala-Gly-MePhe-Gly-ol (DAMGO). In addition, [Dmt1]DALDA was 3000-fold more potent than morphine when administered intrathecally. A potential problem with peptide analogs as therapeutic agents is their susceptibility to enzymatic degradation in vivo and short elimination half-lives. In this study, we compared the stability of DAMGO, DALDA, and [Dmt1]DALDA after systemic administration in sheep. Peptide concentrations were measured using high performance liquid chromatography-mass spectrometry. When incubated in sheep blood at 37°C, DAMGO, DALDA, and [Dmt1]DALDA were stable over 2 h. When given intravenously to sheep, the apparent volume of distribution was 50 to 80 ml/kg for all three peptides, suggesting that distribution was limited to blood volume. Plasma clearance of DAMGO (223 ml/kg/h) was 10-fold faster than DALDA and [Dmt1]DALDA (24 ml/kg/h), and their elimination half-lives were 0.24, 1.5, and 1.8 h, respectively. The half-lives of DALDA and [Dmt1]DALDA are even longer than morphine or meperidine in sheep. These favorable pharmacokinetic properties of DALDA and [Dmt1]DALDA, together with their μ-selectivity, potency, and long duration of action, make them ideal candidates as opioid analgesics.
Footnotes
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This work was supported, in part, by a multicenter program project grant from the National Institute on Drug Abuse (5PO1 DA08924).
- Abbreviations:
- DAMGO
- H-Tyr-d-Ala-Gly-MePhe-Gly-ol
- DALDA
- H-Tyr-d-Arg-Phe-Lys-NH2
- [Dmt1]DALDA
- H-Dmt-d-Arg-Phe-Lys-NH2
- Dmt
- 2′,6′-dimethyltyrosine
- DPDPE
- H-Tyr-c[d-Pen-Gly-Phe-d-Pen]-OH
- MS
- mass spectrometry
- CL
- clearance
- Received November 21, 2000.
- Accepted March 13, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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