Comparisons of in Vivo and in Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

Ferenc Zádor, Amir Mohammadzadeh, Mihály Balogh, Zoltán S. Zádori, Kornél Király, Szilvia Barsi, Anna Rita Galambos, Szilvia B. László, Barbara Hutka, András Váradi, Sándor Hosztafi, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani

Research output: Article

1 Citation (Scopus)

Abstract

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Original languageEnglish
Article number1370
JournalMolecules
Volume25
Issue number6
DOIs
Publication statusPublished - jan. 1 2020

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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    Zádor, F., Mohammadzadeh, A., Balogh, M., Zádori, Z. S., Király, K., Barsi, S., Galambos, A. R., László, S. B., Hutka, B., Váradi, A., Hosztafi, S., Riba, P., Benyhe, S., Fürst, S., & Al-Khrasani, M. (2020). Comparisons of in Vivo and in Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate. Molecules, 25(6), [1370]. https://doi.org/10.3390/molecules25061370