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

Article abstract of DOI:10.1021/jm00049a010

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, 5>Dyn A_1-11-NH2, and 11>Dyn A_1-11-NH2 were synthesized as standards.Several of these cyclic analogues, especially c5,D-Cys¹¹>Dyn A_1-11-NH2, c5,L- or D-Pen¹¹>Dyn A_1-11-NH2, c5,L-Pen¹¹>Dyn A_1-11-NH2 and c5,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.