22207-84-7Relevant academic research and scientific papers
Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the α3β4 nicotinic acetylcholine receptor (nAChR)
Kombo, David C.,Hauser, Terry A.,Grinevich, Vladimir P.,Melvin, Matthew S.,Strachan, Jon-Paul,Sidach, Serguei S.,Chewning, Joseph,Fedorov, Nikolai,Tallapragada, Kartik,Breining, Scott R.,Miller, Craig H.
, p. 1450 - 1455 (2013)
We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3β4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3β4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC50 values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3β4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3β4 receptor subtype. Docking into the orthosteric binding site of a α3β4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.
Directional Intermolecular Interactions for Precise Molecular Design of a High- Tc Multiaxial Molecular Ferroelectric
Yang, Chen-Kai,Chen, Wang-Nan,Ding, Yan-Ting,Wang, Jing,Rao, Yin,Liao, Wei-Qiang,Xie, Yongfa,Zou, Wennan,Xiong, Ren-Gen
, p. 1781 - 1787 (2019)
Quasi-spherical molecules have recently been developed as promising building blocks for constructing high-performance molecular ferroelectrics. However, although the modification of spherical molecules into quasi-spherical ones can efficiently lower the crystal symmetry, it is still a challenge to precisely arouse a low-symmetric polar crystal structure. Here, by introducing directional hydrogen-bonding interactions in the molecular modification, we successfully reduced the cubic centrosymmetric Pm3m space group of [quinuclidinium]ClO4 at room temperature to the orthorhombic polar Pna21 space group of [3-oxoquinuclidinium]ClO4. Different from the substituent groups of -OH, -CH3, and -CH2, the addition of a -O group with H-acceptor to [quinuclidinium]+ forms directionally N-H?O-C hydrogen-bonded chains, which plays a critical role in the generation of polar structure in [3-oxoquinuclidinium]ClO4. Systematic characterization indicates that [3-oxoquinuclidinium]ClO4 is an excellent molecular ferroelectric with a high Curie temperature of 457 K, a large saturate polarization of 6.7 μC/cm2, and a multiaxial feature of 6 equiv ferroelectric axes. This work demonstrates that the strategy of combining quasi-spherical molecule building blocks with directional intermolecular interactions provides an efficient route to precisely design new eminent molecular ferroelectrics.
PROGRANULIN MODULATORS AND METHODS OF USING THE SAME
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Paragraph 0291, (2021/04/30)
Provided herein are compounds of formula (I) that modulate progranulin and methods of using the compounds in progranulin- associated disorders, such as Frontotemperal lobe dementia (FTLD).
