Synthesis and biological activity of dynorphin‐(1 ‐ 13) and analogs substituted in positions 8 and 10

Publisher Website
Google Scholar
Abstract
Dynorphin-(1-13) (Dyn-(1-13)) and various analogs substituted in positions 8 and 10 were synthesized by the solid-phase technique and analyzed for their ability to inhibit the electrically evoked contraction of the guinea pig ileum (GPI) and to compete with the binding of [3H]-ethylketocyclazocine (EKC, .kappa. ligand), [3H]-[D-Ala2, MePhe4-Gly-ol5]-enkephalin (DAGO), .mu. ligand) and [3H]-[D-Ser2, Thr6]-Leu-enkephalin (DSLET, .delta. ligand) to membrane preparations of the guinea pig cerebellum or rat brain. Introduction of Ala in position 8 decreased the activity of the peptide on the GPI by 50% but induced a 2.22-fold increase in its affinity for the .kappa. receptor ([3H]-EKC binding displacement from guinea pig cerebellum; Ki of 0.05 nM as compared with 0.11 nM for Dyn-(1-13)). On the other hand, the ability of [Ala8]-Dyn-(1-13) to displace the binding of [3H]-DSLET from rat brain membranes was decreased by a factor of 1.7 while its affinity for the .mu. receptor was not greatly affected ([3H]-DAGO displacement; Ki of 0.44 nM as compared with 0.50 nM for Dyn-(1-13)). Replacement of position 8 by D-Ala caused similar changes in the activity of the peptide but the increase in its affinity for the .kappa. site was somewhat smaller (Ki of 0.08 nM as compared with 0.11 nM). [D-Pro10]-Dyn-(1-13) was equipotent to [Ala8]-Dyn-(1-13) in the GPI but its affinity for the .mu. binding site was decreased by a factor of 2.7 as compared with Dyn-(1-13). The affinity of [D-Pro10]-Dyn-(1-13) for the other binding sites (.kappa. and .delta.) was not greatly affected. Replacement of positions 8 or 10 by Trp or D-Trp decreased the activity on the GPI by more than 50% as well as the affinity for most receptor types. These data indicate that the selectivity of Dyn(1-13) for the .kappa. opioid receptor can be increased either by increasing its affinity for the .kappa. binding site ([Ala8]-Dyn-(1-13)) or lowering its potency for other binding sites, [Ala8]-Dyn-(1-13) being less potent on .delta. sites and [D-Pro10]-Dyn-(1-13) less potent on .mu. sites.