Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
/ administration & dosage
Analgesics, Non-Narcotic
/ administration & dosage
Animals
Anti-Anxiety Agents
/ administration & dosage
Antidepressive Agents
/ administration & dosage
Behavior, Animal
/ drug effects
Benzamides
/ administration & dosage
Drug Development
Drug Evaluation, Preclinical
Male
Narcotic Antagonists
/ administration & dosage
Piperidines
/ administration & dosage
Pyrrolidines
/ administration & dosage
Rats
Rats, Sprague-Dawley
Receptors, Opioid, kappa
/ agonists
Tetrahydroisoquinolines
/ administration & dosage
JDTic
488
ICSS
LY-2456302
U50
analgesia
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
01
07
2019
revised:
09
09
2019
accepted:
10
10
2019
pubmed:
16
10
2019
medline:
13
5
2020
entrez:
16
10
2019
Statut:
ppublish
Résumé
New 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. We 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). In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. These 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.
Sections du résumé
BACKGROUND
New 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.
METHODS
We 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).
RESULTS
In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay.
CONCLUSIONS
These 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.
Identifiants
pubmed: 31613314
pii: 5587707
doi: 10.1093/ijnp/pyz054
pmc: PMC7145521
doi:
Substances chimiques
7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide
0
Analgesics, Non-Narcotic
0
Anti-Anxiety Agents
0
Antidepressive Agents
0
Benzamides
0
Narcotic Antagonists
0
Piperidines
0
Pyrrolidines
0
Receptors, Opioid, kappa
0
Tetrahydroisoquinolines
0
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
67198-13-4
Aticaprant
DE4G8X55F5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
735-745Subventions
Organisme : NIMH NIH HHS
ID : R01 MH063266
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.
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