Opioid receptor antagonist properties of the mu opioid receptor selective peptide, BOC-Tyr-Lys-Lys-Trp-Trp-NH2 and its systematically modified analogues were determined in guinea pig ileum, mouse vas deferens and rabbit vas deferens bioassays to locate the necessary structural features to develop kappa receptor selective antagonist(s) of substantial affinity. Replacing the tyrosine residue by phenylalanine as well as increasing the lipophilicity of the C-terminal by isoamylamide substitution yielded enhanced kappa receptor affinity. The presence of the C-terminal lipophilic Trp-Trp-NH2 region is necessary as revealed from the equilibrium dissociation constant values. Recognizing that only one lysine residue is required for the antagonist activity led to the synthesis of the tetrapeptide BOC-Tyr-Lys-Trp-Trp-NH2 having a kappa/mu selectivity of 22 and a Ke of 5.4 microM.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1006/bbrc.1994.2070 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as a drug of abuse . It is well established that fentanyl acts as a μ-opioid receptor agonist, signaling through Gα intracellular pathways to inhibit electrical excitability, resulting in analgesia and respiratory depression . However, fentanyl uniquely also triggers muscle rigidity, including respiratory muscles, hindering the ability to execute central respiratory commands or to receive external resuscitation.
View Article and Find Full Text PDFThe U.S. opioid epidemic is an extraordinary public health crisis that started in 1990 and significantly accelerated in the last decade.
View Article and Find Full Text PDFLarge library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines.
View Article and Find Full Text PDFKetamine Infusion as an Adjunct to Opioid Analgesia in Pediatric Patients with High-Risk Neuroblastoma Undergoing Treatment with Dinutuximab: Adverse Effects and Safety in a Non-ICU Setting.
J Pain Res
January 2025
Department of Pediatrics- Division of Pediatric Oncology, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA.
Introduction: Anti-GD2 immunotherapy has improved outcomes for children with high-risk neuroblastoma (HRNBL). Dinutuximab promotes complement-mediated reaction against disialoganglioside GD2, which is expressed in peripheral nerves and over-expressed in neuroblastoma. Dinutuximab is associated with ≥grade 3 neuropathic pain.
View Article and Find Full Text PDFNovel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor.
Bioorg Med Chem Lett
January 2025
Contineum Therapeutics, 3565 General Atomics Court, Suite 200, San Diego, CA 92121, United States.
Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure-activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC = 14 nM, 83 % E) that did not elicit a β-arrestin-2 recruitment functional response (E < 10 %).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!