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 (K_i^δ/K_i^μ> 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.