Design, Synthesis, and Biological Properties of Highly Potent Cyclic Dynorphin A Analogues. Analogues Cyclized between Positions 5 and 11

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A_1-11-NH₂, exhibited unexpected selectivities for the κ and μ receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A_1-11-NH₂ analogues incorporating the sulfydryl containing amino acids l- and d-Cys and l- and d-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A_1-11-NH₂, [d-Leu⁵]Dyn A_1-11-NH₂, and [d-Lysn¹¹]Dyn A_1-11-NH₂ were synthesized as standards. Several of these cyclic analogues, especially c[Cys⁵, D-Cys¹¹] Dyn A_1-11NH₂, c[Cys⁵, l- or d-Pen₁₁]Dyn A_1-11-NH₂, c[Pen⁵, l-Pen₁₁]Dyn A_1-11-NH₂ and c[Pen⁵, l- or d-Cys₁₁]Dyn A_1-11-NH₂, retained the same affinity and selectivity (vs the μ and δ receptors) as the parent compound Dyn A_1-11-NH₂ in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at κ opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the κ, μ, or δ central receptors.