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.

Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and Their Pharmacologies

“…The opioid ligands bind with opioid receptors with three main types of pharmacophore bonds: ionic attraction, π–π interaction, and hydrogen bonding, termed the message site . The above obtained potent OX 1 R antagonists were hardly bound with the opioid receptors because of the absence of the basic nitrogen and the phenolic hydroxy group. ,, The ion formed by the protonation on the basic 17-nitrogen and the acidic hydrogen derived from the 3-phenolic hydroxyl group seemed to disrupt the fitting to the orexin receptor.…”

“…The only 17-Boc derivative 26 had a rather higher affinity for the KOR ( K i = 184 nM) despite containing the 3-methoxy group. These data from the binding assays suggest that the above obtained 3-methoxy­sulfonamide derivatives could remove the serious side effects derived from the opioid receptors (addiction, constipation, respiratory depression from MOR, catalepsy from DOR, and especially sedation and aversion from KOR), although the structures of these OX 1 R antagonists were derived from the potent KOR agonist, nalfurafine ( 12 ) …”

“…We have been interested in the interaction of the OX 1 R with opioid receptors on the basis of our long history in the opioid research field and also intrigued by the biological relevance for the coexpression of excitatory orexin and inhibitory dynorphin ( 11 , endogenous κ opioid agonist) and the coexistence of their opposing effects within the same vesicle in the orexin neuron . To obtain specific ligands for clarifying the potential role for their coexistence, we attempted to design and synthesize OX 1 R antagonists derived from κ opioid receptor (KOR) ligands.…”

CsPbBr3 perovskite quantum dots as a visible light photocatalyst for cyclisation of diamines and amino alcohols: an efficient approach to synthesize imidazolidines, fused-imidazolidines and oxazolidines

“…[5][6][7][8] Several strategies have been reported to assemble these heterocyclic motifs which include: [3 + 2]-annulation reactions, 9,10 1,3-dipolar cycloaddition, 11,12 the condensation reaction of 1,2-amino alcohol/diamine derivatives with carbonyl compounds, 5,13,14 the aza-Wacker reaction, 15 etc. In 2011, Xiao et al reported sp 3 C-H bond functionalisation of the N-CH 2 Ph (benzylic) group and subsequent intramolecular cyclisation of 1-2-diamines using a Ru-based photocatalyst in the presence of a strong base (Fig. 2a).…”

“…16 The cyclisation of amines and amino alcohols has emerged as an attractive approach to synthesize imidazolidines, fused-imidazolines and oxazolidines. [16][17][18][19] The synthesis of the above heterocyclic motifs via selective sp 3 C-H bond functionalisation of the N-Me (alkyl) group is considered a challenging task due to its high thermodynamic stability. 20 Most of the above strategies involve the use of expensive metal complexes, reactive oxidants and elevated temperature (Fig.…”