Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats
| Autor: | Elena H. Chartoff, Maria Mavrikaki, Hugh Rosen, Edward Roberts, Sarah Page, Tania Lintz, F Ivy Carroll, Daniel Puttick, William A. Carlezon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Agonist
Male Pyrrolidines medicine.drug_class Narcotic Antagonists Analgesic Central nervous system Drug Evaluation Preclinical Pharmacology κ-opioid receptor Regular Research Articles Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Development Piperidines Tetrahydroisoquinolines medicine Animals Pharmacology (medical) LY-2456302 030304 developmental biology 0303 health sciences U50 Behavior Animal business.industry Receptors Opioid kappa 3 4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide (trans)-Isomer Anhedonia analgesia JDTic Analgesics Non-Narcotic Antidepressive Agents Rats Psychiatry and Mental health medicine.anatomical_structure Nociception chemistry Anti-Anxiety Agents Benzamides ICSS Antidepressant medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Neuropsychopharmacology |
| ISSN: | 1469-5111 1461-1457 6795-3964 |
| Popis: | BackgroundNew treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development.MethodsWe screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964).ResultsIn the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 ConclusionsThese results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test. |
| Databáze: | OpenAIRE |
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