Xing-hai Wang

Bis-(−)-nor-meptazinols as Novel Nanomolar Cholinesterase Inhibitors with High Inhibitory Potency on Amyloid-β Aggregation

Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.

Highly selective and potent μ opioid ligands by unexpected substituent on morphine skeleton

Unexpected substituent on the well-known morphine skeleton is described to be account for highly selective and potent mu opioid ligands, which is strongly connected to substituted aromatic groups on this omitted 8alpha-position.

(3S,4S)-3-Ethyl-4-hydr­oxy-3-(3-methoxy­phen­yl)-1-methyl­azepan-1-ium d-tartrate dihydrate

In the title compound, C16H26NO2 +·C4H5O6 −·2H2O, a meptazinol derivative, three C atoms of the azepane ring are disordered over two positions, with site-occupancy factors of 0.80 and 0.20; the major disorder component adopts a twist-chair conformation, while the minor component has a chair conformation. The benzene ring is axially substituted on the heterocyclic ring, resulting in a folded conformation of the cation. The absolute configuration was determined with reference to d-tartaric acid. The crystal structure is stabilized by an extensive network of intra- and intermolecular O—H⋯O hydrogen bonds.

Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores.

AbstractAim:To further investigate the analgesic pharmacophore of (+)-meptazinol.Methods:Two different opioid pharmacophores, Pharm-I and Pharm-II, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of (+)-meptazinol (Conformer-I and Conformer-II) detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis.Results:Conformer-I fit Pharm-I from typical opiates well. However, Conformer-II fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3-c] pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine (eg, meperidine) with one conformer absolutely overwhelming, the (+)-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results.Conclusion:(+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.

Theoretical and NMR investigations on the conformations of ( − )-meptazinol hydrochloride in solution

( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-meptazinol complex, two different and naturally stable conformers of ( − )-meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group

Abstract7α-Phenyl-6α,14α-endo-etheno-tetrahydrothebaine is an analogue of morphine but with much weaker affinity and efficacy to opioid receptors. Three compounds with o-, m- and p-amino substitution on its 7α-phenyl group were designed and synthesized to evaluate their κ-opioid receptor agonistic activity and antinociceptive effect. The introduction of amino group greatly increased the binding activity to κ-opioid receptor but only compound with p-substitution showed agonistic activity with potency similar to the marketed κ agonist butorphanol. In vivo antinociceptive test showed that compound with p-amino substitution displayed highest antinociceptive activity while compounds with o-, m-amino substitution showed partial or little analgesia effects. All these data indicate that p-amino substitution conferred κ agonist activity, suggesting that 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaines with a p-amino substitution may contain a novel pharmacophore component and could be considered as a leading compound for novel antinociceptive agents.

(3S,4R)-3-Ethyl-4-hydr­oxy-3-(3-methoxy­phen­yl)-1-methyl­azepanium (2R,3R)-2,3-bis­(benzo­yloxy)-3-carboxy­propionate

The crystal structure of the title compound, C16H26NO2 +·C18H13O8 −, is stabilized by an extensive network of classical N—H⋯O and O—H⋯O hydrogen bonding. The crystal structure also shows an ammonium-driven diastereoisomerism.