Blockade of non-opioid excitatory effects of spinal Dynorphin A at bradykinin receptors

Dynorphin A (Dyn A) is an endogenous opioid peptide that produces neuroinhibitory (antinociceptive) effects via m, d, and k opioid receptors. However, under chronic pain conditions, up-regulated spinal Dyn A can also interact with bradykinin receptors (BRs) to promote hyperalgesia through a neuroexcitatory (pronociceptive) effect.  These excitatory effects cannot be blocked by an opioid antagonist, and thus are non-opioid in nature. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, and provided an opportunity to discover a novel potential neuroexcitatory target. Systematic structure-activity relationship (SAR) studies discovered a minimum pharmacophore of Dyn A, [des-Arg7]-Dyn A-(4-11) LYS1044 for antagonist activity at the BRs, along with insights into the key structural features for BRs recognition, i.e., amphipathicity.  The des-Tyr fragment of dynorphin does not bind to opioid receptors.  Intrathecal administration of des-Tyr dynorphin produces hyperalgesia reminiscent of behaviors seen in peripheral neuropathic pain models and at higher doses, neurotoxicity. Our lead ligand LYS1044 blocked Dyn A-(2-13)-induced neuroexcitatory effects in naïve animals and reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in animals with experimental neuropathic pain. Based on these results, ligand LYS1044 might inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A that are seen in experimental models of neuropathic pain and that likely promote excitation mediated by BRs in the spinal cord

Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Structure–Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the κ Opioid Receptor

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure–activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg⁷ residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg⁷]­Dyn A analogues found that Arg⁷ is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg⁷]­Dyn A­(1–9)-NH₂ is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, <b>14</b>, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse