Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities
| Autor: | Irina D. Pogozheva, Larisa Yeomans, Jessica P. Anand, Emily M. Jutkiewicz, John R. Traynor, Henry I. Mosberg, Nicholas W. Griggs, Aubrie A. Harland |
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| Rok vydání: | 2015 |
| Předmět: |
Agonist
Male medicine.drug_class Peptidomimetic Receptors Opioid mu Biological Availability CHO Cells Pharmacology Article Substrate Specificity Mice Radioligand Assay Structure-Activity Relationship Cricetulus In vivo Opioid receptor Cricetinae Receptors Opioid delta Drug Discovery medicine Structure–activity relationship Animals Humans Receptor Pain Measurement Analgesics Dose-Response Relationship Drug Chemistry Receptors Opioid kappa Antagonist Acetylation Mice Inbred C57BL Opioid Guanosine 5'-O-(3-Thiotriphosphate) Drug Design Molecular Medicine Injections Intraperitoneal medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 58(22) |
| ISSN: | 1520-4804 |
| Popis: | In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h. |
| Databáze: | OpenAIRE |
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