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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-03, Vol.25 (6), p.1370
• Main Authors: Zádor, Ferenc, Mohammadzadeh, Amir, Balogh, Mihály, Zádori, Zoltán S, Király, Kornél, Barsi, Szilvia, Galambos, Anna Rita, László, Szilvia B, Hutka, Barbara, Váradi, András, Hosztafi, Sándor, Riba, Pál, Benyhe, Sándor, Fürst, Susanna, Al-Khrasani, Mahmoud
• Format: Article
• Language: English
• Subjects: 14-methoxycodeine-6-o-sulfate; Affinity; Analgesics; Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Animals; Binding, Competitive; Bioassays; Codeine; Codeine - chemical synthesis; Codeine - chemistry; Codeine - pharmacology; Codeine - therapeutic use; codeine-6-o-sulfate; Competition; Constipation; Freund's Adjuvant; Gastrointestinal Transit - drug effects; Hyperalgesia; In vitro methods and tests; In vivo methods and tests; Inflammation; Inflammation - drug therapy; Injections, Intraventricular; Male; Mice; Morphine; Naloxone; Naloxone - pharmacology; Naloxone - therapeutic use; Narcotics; Nervous system; Nociception - drug effects; Opioid receptors; Pain; Pain - drug therapy; Pain perception; peripheral antinociception; Pharmacology; Proteins; Rats, Wistar; Receptors, Opioid, mu - metabolism; Spinal cord; Sulfates; Vas deferens
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25061370

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6- -sulfate (14-OMeC6SU), compared to the reference compounds codeine-6- -sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [ S]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.