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Article

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

1
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
2
Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
3
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u., 9. H-1092 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(6), 1370; https://doi.org/10.3390/molecules25061370
Received: 15 February 2020 / Revised: 13 March 2020 / Accepted: 15 March 2020 / Published: 17 March 2020
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. View Full-Text
Keywords: peripheral antinociception; 14-methoxycodeine-6-O-sulfate; codeine-6-O-sulfate peripheral antinociception; 14-methoxycodeine-6-O-sulfate; codeine-6-O-sulfate
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MDPI and ACS Style

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. Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate. Molecules 2020, 25, 1370. https://doi.org/10.3390/molecules25061370

AMA Style

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

Chicago/Turabian Style

Zádor, Ferenc; Mohammadzadeh, Amir; Balogh, Mihály; Zádori, Zoltán S.; Király, Kornél; Barsi, Szilvia; Galambos, Anna R.; László, Szilvia B.; Hutka, Barbara; Váradi, András; Hosztafi, Sándor; Riba, Pál; Benyhe, Sándor; Fürst, Susanna; Al-Khrasani, Mahmoud. 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, no. 6: 1370. https://doi.org/10.3390/molecules25061370

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