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Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.
Page, Sarah; Mavrikaki, Maria M; Lintz, Tania; Puttick, Daniel; Roberts, Edward; Rosen, Hugh; Carroll, F Ivy; Carlezon, William A; Chartoff, Elena H.
Afiliación
  • Page S; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Mavrikaki MM; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Lintz T; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Puttick D; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Roberts E; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
  • Rosen H; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
  • Carroll FI; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Carlezon WA; Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA.
  • Chartoff EH; Research Triangle Institute, Research Triangle Park, NC.
Int J Neuropsychopharmacol ; 22(11): 735-745, 2019 11 01.
Article en En | MEDLINE | ID: mdl-31613314
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Piperidinas / Pirrolidinas / Ansiolíticos / Conducta Animal / Benzamidas / Receptores Opioides kappa / Analgésicos no Narcóticos / 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero / Tetrahidroisoquinolinas / Antidepresivos Idioma: En Revista: Int J Neuropsychopharmacol Asunto de la revista: NEUROLOGIA / PSICOFARMACOLOGIA Año: 2019 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Piperidinas / Pirrolidinas / Ansiolíticos / Conducta Animal / Benzamidas / Receptores Opioides kappa / Analgésicos no Narcóticos / 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero / Tetrahidroisoquinolinas / Antidepresivos Idioma: En Revista: Int J Neuropsychopharmacol Asunto de la revista: NEUROLOGIA / PSICOFARMACOLOGIA Año: 2019 Tipo del documento: Article