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.
