14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Abstract

A B S T R A C T14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-OMeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. binding. In addition, 14-O-MeM compared to morphine showed higher affinity for μ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value.

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

“…Accordingly, 14-OMeC6SU showed the highest affinity for MOR compared to C6SU or codeine and displayed similar binding properties as described in earlier studies, together with codeine [14,17,27]. Our results correspond well with previous data and confirm that the 14-O-methylation of the morphinan structure significantly enhances not only the affinity for MOR, but also for DOR and KOR [4,6,20,22,23]. Other research groups have reported that 14-O-methyl analogs of oxymorphone have improved affinity, agonist activity and antinociceptive potency compared to their parent compound, oxymorphone [36].…”

“…The novel codeine analog 14-OMeC6SU, CS6U and the parent compound codeine were tested for opioid receptor binding affinity and selectivity in in vitro radioligand competition binding assays using prototypic selective radioligands for MOR and DOR in rat brain membrane homogenates, or for KOR in guinea pig brain membrane homogenates. The prototypic opioid ligands displayed high affinity as expected and are in accordance with previous data [20,23].…”

“…In addition, 14-OMeC6SU was also measured in rat spinal cord and compared to MOR and DOR selective agonists. The agonist properties (EC 50 , E max ,) of the reference compounds were as expected and as reported previously [20,23]. Additionally, in rat brain tissues we aimed to demonstrate whether U-69593 can produce measurable KOR activity.…”

“…The parent compound codeine showed poor affinity for MOR and none for DOR and KOR ( Figure 2 and Table 1). (One-sample t test) the total specific radioligand binding (100%), thus the Ki value cannot be interpreted (N.D. not determined); 5 adopted from [23]; 6 indicates the unlabeled form of the radioligands and represent a control for the assay (μ: DAMGO : IleDelt II, : U-69593); * compared to codeine (One-way ANOVA, with Sidak's multiple comparison test; ** P < 0.01, *** P < 0.001). Table 1.…”

“…Such compounds have been demonstrated to have reduced central side effects as well [5,21]. Extreme increase in the affinity, efficacy and analgesic activity was measured for 14-methoxy analogs of morphine or oxymorphone compared to the parent compounds [4,6,20,22,23].…”