The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety

Abstract

In order to improve metabolic stability, a ring structure with a cystine moiety was introduced into TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)Bzl]), which is a lead compound of our developing bifunctional peptide possessing opioid agonist and NK1 antagonist activities. TY038 (Tyr-cyclo[D-Cys-Gly-Phe-Met-Pro-D-Cys]-Trp-NH-[3',5'-(CF(3))(2)Bzl]) was found as a highly selective delta opioid agonist over mu receptor in conventional tissue-based assays, together with an effective NK1 antagonist activity and good metabolic stability with more than 24h half life in rat plasma.

Figure 1

Sequences of opioid and NK1 receptor peptides.

Figure 2

Comparison of the in vitro metabolic stability for 1 (black), 2 (blue), 3 (green), 4 (red) and 5 (purple) incubated in rat plasma at 37°C. Calculated half lives of peptide derivatives (T_1/2) were 4.8 h for 1, 4.9 h for 3 and > 6 h for 2, 4 and 5. 70 ± 1 % of 6 was found intact after 24 h incubation. The samples were tested in at least two independent experiments and the mean values were displayed.