Drug design and synthesis of a novel κ opioid receptor agonist with an oxabicyclo[2.2.2]octane skeleton and its pharmacology

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

“…2), the C-ring would assume the boat form, thereby elevating the amide side chain to bind the κ receptor. 4,5,21,22) Based on this hypothesis, we designed and synthesized KNT-63 with an oxabicyclo[2.2.2] octane skeleton ( Fig. 1), and confirmed its high affinity for the κ receptor.…”

“…1), and confirmed its high affinity for the κ receptor. 5) We also proposed a new three-dimensional pharmacophore model applicable to some κ agonists with various chemotypes. 21,22) Our new pharmacophore model of κ agonists supported the proposed active conformation of nalfurafine and indicated that the binding modes of κ agonists to the κ receptor could be classified into four types.…”

“…1) Narcotic addiction is believed to be derived from the μ receptor type, and therefore δ and κ types are promising drug targets for analgesics without addiction. To obtain ideal analgesics without addiction and other side effects derived from the μ receptor, we have synthesized various kinds of naltrexone derivatives and have reported selective ligands for κ [2][3][4][5][6][7][8][9] and δ [10][11][12][13][14] receptors. Quite recently, one of our designed κ selective agonists, nalfurafine hydrochloride (TRK-820, 2,3,6,8,9) Fig.…”

Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: Synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet)

“…Procedures similar to those previously reported 16 The j selectivity of SYK-134 (7a) and SYK-135 (8a) can be interpreted in terms of their possible conformation: the dipole-dipole repulsion between 4,5-epoxy moiety and the cap structure would raise the 1,3,5-trioxazatriquinane structure to the upper side of the C-ring (Fig. 4A), which would resemble the active conformation of nalfurafine [18][19][20][21] (Fig. 4B) for binding to the j receptor.…”

Synthesis of 6,14-epoxymorphinan derivatives and their pharmacologies

“…We were interested in the difference of the pharmacological effects between TRK-820 and the arylacetamide derivatives, and carried out the conformational analysis of them and detailed SAR investigation of TRK-820 derivatives to develop the working hypothesis that when TRK-820 binds to the j receptor, the C-ring would adopt a boat conformation. 8,23,24 According to the above hypothesis, the 14-hydroxy group may interact with the 6-amide side chain in TRK-820 and this orientation of the amide side chain would assist the adaptation of the ligand to the j receptor (Fig. 2).…”