Peripherally-Selective K-Opioid Agonist EMD 61753: A Comprehensive Pharmacological Overview

The new diarylacetamide compound, EMD 61753, has been evaluated for its pharmacological characteristics and compared to other k-opioid receptor agonists. It shows a high affinity and selectivity for k-opioid receptors, with a full agonist effect in an in vitro assay using rabbit vas deferens preparation. When administered systemically, EMD 61753 is found in higher concentrations in the lungs, liver, adrenal glands, and kidneys, with low penetration into the central nervous system (CNS).

In terms of central activity, EMD 61753 demonstrates limited effectiveness. It only reverses haloperidol-induced DOPA accumulation in rats at a high dose, and it extends hexobarbitone-induced sleeping in mice at threshold doses. Furthermore, it impairs motor performance in rats with a specific dose-dependent value. The compound also produces dose-dependent antinociception in mice and rats, which is reversible by naloxone. Notably, its effect in the hyperalgesic pressure test is potent and reversible by the k-opioid antagonist, indicating a peripheral opioid receptor mediation.

EMD 61753 also inhibits cutaneous plasma protein extravasation in a dose-dependent manner, an effect that is completely antagonized by norbinaltorphimine. It induces diuresis in non-hydrated and saline-loaded rats at certain doses. Importantly, it does not inhibit the prostaglandin-mediated fall in blood pressure induced by arachidonic acid, suggesting that its in vivo effects and those of its metabolites are not due to cyclo-oxygenase inhibition.

Overall, EMD 61753 is identified as a potent, selective, and orally effective full K-opioid receptor agonist with limited CNS penetration for central effects. Its peripherally mediated actions against hyperalgesia and neurogenic inflammation are likely through opioid receptors on sensory nerve endings.