Highly .kappa. receptor-selective dynorphin A analogs with modifications in position 3 of dynorphin A(1-11)-NH2

Abstract

The heptadecapeptide dynorphin A (Dyn A(1-17); H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH) was first isolated from porcine pituitary and recognized as a potent opioid a g o n i~t .~-~ It is now well established that there are at least three types of opioid receptors, namely, p, 6 , and K .~-~ However, the physiological and pharmacological roles of these receptors still need clarification, thus requiring the design and synthesis of highly potent and selective ligands. Research in this area has expanded rapidly in the past decade, with considerable effort devoted to the development of 6 and p opioid receptorselective peptide ligands primarily based onThe potential of targeting the K opioid receptor as an effector for analgesia has yet to be explored in detail.12 Previous structure-activity studies have shown that the truncated derivative, dynorphin A(l-ll)-NHz, retains the high binding potency of dynorphin A at the K receptor. Thus we and others have primarily used Dyn A(l-ll)-NHz as a template to examine the structure-activity relationships of dynorphin.13J4 Since Tyr' and Phe4 are reported to be important for opioid agonist activity, the effects of the glycine residues in positions 2 and 3 of Dyn A on the relative orientations of the two aromatic rings may be biologically i m~0 r t a n t . l~ To assess these possible effects, we have substituted Gly3 by D-and L-alanine residues to form the linear peptides [D-Ala3]Dyn A(1-11)-NHz and [Ala31Dyn A(l-ll)-NHz. We report here that both analogues are very potent for K receptors and very selective for K vs p and K vs 6 receptors. These results suggest that substitution of lipophilic residues and/or certain D-amino acids at position 3 of Dyn A(1-11)-NHz may lead to novel Dyn A analogues which exhibit enhanced selectivities for K receptors, while retaining strong affinities.Peptide Synthesis and Purification. Dynorphin A analogues were synthesized by solid phase methods that were reported previously for the synthesis of other Dyn A analogues.14J5 Side chain-protected Na-Boc amino acids were purchased from Bachem (Torrance, CA), whereas the other amino acids were synthesized by standard methods in our laboratory. The synthesized analogues were purified by RP-HPLC (linear gradient of 10-90% acetonitrile in 0.1% TFA in water over 40 min) and characterized by FAB-MS and amino acid analysis. The purity of the synthetic peptides was assessed by TLC (single spot in four different solvent

Dynorphin a Analogs for the Treatment of Chronic Neuropathic Pain

“…Anticonvulsants such as pregablin and gabapentin are often prescribed and are effective for patients with postherpetic neuralgia, fibromyalgia and diabetic peripheral neuropathy [5]. For over 40 years, antidepressants such as tricycles, selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors have been used for the treatment of neuropathic pain and show efficacy for some patients [6]. Steroids are generally used as an adjunct therapy with opioids and are beneficial to patients with metastatic bone pain, visceral pain and neuropathic pain [7].…”

“…0.63 [15,51] Dyn A-(1-11)NH 2 H-Y-G-G-F-L-R-R-I-R-P-K-NH 2 1/17/44 1.1 ± 0.3 [40] [DAla 3 ] DynA-(1-11) NH 2 H-Y-G-a-F-L-R-R-I-R-P-K-NH 2 1/350/1300 8.1 ± 2.3 [40] [DPro] DynA-(1-11)…”

Development of highly potent and ective dynorphin A analogues as new medicines

“…Hruby's team has continued in the design and syntheses of various Dyn A analogues, including linear, disulphide‐bridged and lactam‐bridged peptides or peptidomimetics. Bioactive assay were performed, using IC 50 values of GPI and BVD for binding affinities and potency and comparing IC 50 between GPB (central nervous system, CNS) and BPI (peripheral) for selectivities at the κ ‐ and μ ‐opioid receptors (Tables 1–3; 23,31–36,51).…”

Benzomorphan alkaloids: Natural peptidomimetics of opioid peptide pharmacophores

“…Surprisingly, 20 years after the discovery of the endogenous opioid peptides only a few general correlations between nonpeptide and peptide ligands have been defined. The most important discoveries, such as creation of selective ligands for 5 [2,3], I-t [4,5], and n [6,7] receptors, were done independently in peptide and alkaloid research groups. Differences in peptide and alkaloid bioactivities, metabolic pathways, and permeabilities impede cross-correlation of the two types of ligands.…”