341989-93-3Relevant academic research and scientific papers
Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel
Yu, Zhiyi,Van Veldhoven, Jacobus P.D.,'T Hart, Ingrid M.E.,Kopf, Adrian H.,Heitman, Laura H.,Ijzerman, Adriaan P.
, p. 50 - 59 (2015/11/23)
We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [3H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.
Synthesis and biological evaluation of XB-1 analogues as novel histamine H3 receptor antagonists and neuroprotective agents
Bao, Xiaofeng,Jin, Yanyan,Liu, Xiaolu,Liao, Hong,Zhang, Luyong,Pang, Tao
, p. 6761 - 6775 (2014/02/14)
A novel class of H3 receptor antagonists, XB-1 analogues based on benzophenone or oxydibenzene scaffolds were synthesized, and their biological activities were evaluated to determine their in vitro neuroprotective effects against Aβ25-35-induced damage in primary cortical neurons and against glutamate-induced neuronal injury in primary cerebellar granule neurons. The results indicated that all of the tested analogues displayed neuroprotective activity at 0.1 μM or 1 μM. These findings may provide new insights into the development of novel promising H3 receptor antagonists with potential neuroprotective activity.
Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands
Sasse, Astrid,Ligneau, Xavier,Sadek, Bassem,Elz, Sigurd,Pertz, Heinz H.,Ganellin, C. Robin,Arrang, Jean-Michel,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
, p. 45 - 52 (2007/10/03)
Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or SNAr reaction. Most of the title compounds possess high antagonist potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta′-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta′-iodinated derivative demonstrated high selectivity toward the histamine H3 receptor.
