Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

Abstract

We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m-hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (−)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the κ opioid receptor (KOR). Subcutaneously administered (−)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist.

Synthesis of Novel Triplets with a 1,3,5‐Trioxazatriquinane Skeleton and Their Pharmacologies for Opioid Receptors

“…On the other hand, SYK‐146 can be synthesized in only four steps. The enantiomers 22c were separated by semipreparative HPLC (hexane/EtOH = 80:20, flow rate 1.9 mL/min, UV detection at 285 nm, CHIRALPAK IB column (10 ϕ × 250 nm)), resulting in the isolation of (+) ‐22c ( t R = 22.2 min) and (−) ‐22c ( t R = 18.1 min) . The (−)‐22c showed stronger binding affinity for the KOR ( K i = 4.63 nM) than the ( + ) ‐22c , which only weakly bound the KOR.…”

“…According to a previously reported method , we prepared 1,3,5‐trioxazatriquinanes, 38a–c . We commenced with o ‐methoxyacetophenone 27 .…”

“…The binding affinities of the synthesized 1,3,5‐trioxazatriquinanes for the opioid receptors were evaluated with competitive binding assays (Table ). The assays were performed according to a previously described procedure . Nearly all the tested compounds showed low binding affinities to the opioid receptors.…”

“…The functional activities of 42b were assessed with [ 35 S]GTPγS binding assays in CHO cells transfected with human opioid receptors. The procedures used were previously described . Compound 42b showed universal agonistic activity for all three opioid receptors (Table ).…”

“…DAMGO, DPDPE, or U‐69,593 was used as the standard agonist (100%) for MOR, DOR, or KOR, respectively. b) See .…”