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

Abstract

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 A1-11-NH2, exhibited unexpected selectivities for the kappa and mu 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 A1-11-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 A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5,D-Cys11] Dyn A1-11-NH2, c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A1-11-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 kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.

Structure–activity relationships of dynorphin analogs substituted in positions 2 and 3

“…In spite of their high κ affinities (1.5 n M for Sar 2 analog 8 , 2.4 n M for Pro 3 analog 2 ), these ligands are relatively weak agonists or antagonists in the functional assay, which is somewhat surprising. A similar discrepancy between high binding affinity and weak potency in functional assays has been observed in a number of dynorphin analogs 11, 12, 16, 25–27. Different κ receptor subtypes in central vs. peripheral neurons have been proposed as an explanation, because these studies used brain homogenate for the binding assay and guinea pig ileum for the functional assay.…”

Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

“…Interestingly, disulfide bridge containing Dyn A(1-11)-NH 2 analogs [158] revealed an exceptional k and  central receptor affinity in contrast to peripheral k and -opioid receptors [159,160].…”

Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives

“…Initial attempts at using lysine and glutamic acid to close the ring via an amide bond resulted in very poor yields under several different reaction conditions. As the formation of cyclic disulfides from thiol-containing amino acids was previously used successfully to increase the stability and selectivity of opioid peptides [23,24], we decided to use two cysteine residues for ring closure instead. Cyclisation was carried out on the resin using an excess of iodine in DMF.…”