Synthesis and evaluation of novel peripherally restricted κ-opioid receptor agonists
| Autor: | Erin Gauntner, Alan L. Maycock, Virendra Kumar, Patrick J. Little, Michael Koblish, Erik Mansson, Diane L. DeHaven-Hudkins, Susan L. Gottshall, Robert N. DeHaven, Joel A. Cassel, Susan L. Greiner, Jeffrey D. Daubert, Deqi Guo |
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| Rok vydání: | 2005 |
| Předmět: |
Central Nervous System
Pain Threshold Agonist Pyrrolidines Stereochemistry medicine.drug_class Clinical Biochemistry Analgesic Drug Evaluation Preclinical Pain Pharmaceutical Science Carboxamide Pharmacology Biochemistry Chemical synthesis Structure-Activity Relationship In vivo Opioid receptor Drug Discovery medicine Animals Humans Receptor Molecular Biology Analgesics Chemistry Receptors Opioid kappa Organic Chemistry Amides Rats Opioid Molecular Medicine Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 15:1091-1095 |
| ISSN: | 0960-894X |
| Popis: | A series of 3-substituted analogs (3) of the parent kappa agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human kappa opioid receptor with high affinity (K(i)=0.31-9.5 nM) and were selective for kappa over mu and delta opioid receptors. Compounds 3c, d, and 3g-i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral kappa agonist ICI 204448. |
| Databáze: | OpenAIRE |
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