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

doi:10.3390/molecules25061370

Molecules (Mar 2020)

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

Affiliations

Ferenc Zádor: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Amir Mohammadzadeh: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Mihály Balogh: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Zoltán S. Zádori: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Kornél Király: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Szilvia Barsi: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Anna Rita Galambos: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Szilvia B. László: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Barbara Hutka: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
András Váradi: Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u., 9. H-1092 Budapest, Hungary
Sándor Hosztafi: Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u., 9. H-1092 Budapest, Hungary
Pál Riba: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Sándor Benyhe: Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary
Susanna Fürst: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Mahmoud Al-Khrasani: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary

DOI: https://doi.org/10.3390/molecules25061370
Journal volume & issue: Vol. 25, no. 6
p. 1370

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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