title: Synthesis of novel triplets with a 1,3,5-trioxazatriquinane skeleton and their pharmacologies for opioid receptors.
abstract: 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.
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Noriki
authors.initials: N
authors.lastname: Kutsumura
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C581077:1,3,5-trioxazatriquinane; D000701:Analgesics, Opioid; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D011957:Receptors, Opioid
keywords: Capped trimer; Compound libraries; Opioid; Triplet; κ Receptor