Synthesis of novel triplets with a 1,3,5-trioxazatriquinane skeleton and their pharmacologies for opioid receptors.

We designed and synthesized novel triplet molecules with 1,3,5-trioxazatriquinane skeletons. One class comprises double-capped triplets with a morphinan skeleton; the other class comprises simple phenol derivatives with phenethylamine moieties. One compound with m-phenolic hydroxyl group, called SYK-146, is a highly selective, potent agonist for the κ receptor, with activity nearly equivalent to that of U-50488H. The o-phenolic isomer of SYK-146, called SYK-524, showed potent but non-selective agonistic activity for the opioid receptors. We also added several simple phenol derivatives to a library of compounds that target opioid receptors, and they showed high hit rates for the receptor. This library might also be expected to show high hit rates for other receptors.