geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

4-Phenoxybutoxy-substituted heterocycles--a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3


, : 4-Phenoxybutoxy-substituted heterocycles--a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3. European Journal of Medicinal Chemistry 44(5): 1838-1852

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC(50) of 2nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC(50)s of 150 nM to 10 microM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC(50) 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.

US$19.90

PMID: 19056148

DOI: 10.1016/j.ejmech.2008.10.033


Other references

Yang, K.; Kim, J.; Hoppie, B.W.; Harris, R.N., 2011: Characterization of clay minerals in deep subseafloor sediment, South Pacific Gyre; IODP Expedition 329. Deep subseafloor sediment in the South Pacific Gyre was recovered for the first time by Integrated Ocean Drilling Program (IODP) Expedition 329 (2010.10.10-2010.12.13). In the present study, the variations of clay minerals with increasing burial d...

Rossi., 1960: Thrombidiforrues parasites des arbres fruitiers. Travaux du Laboratoire de Zoologie Dijon, 35: 47

Gui, Q-F.; Lu, H-F.; Zhang, C-X.; Xu, Z-R.; Yang, Y-H., 2016: Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model. The intestinal microflora affects inflammation and immunity, not only locally at the mucosal level but also systemically, raising the question of whether the microflora affects inflammatory processes that contribute to cancer and its therapy. Preb...

Harati, M.; Jia, J.; Giffard, Kévin.; Pellarin, K.; Hewson, C.; Love, D.A.; Lau, W.Ming.; Ding, Z., 2010: One-pot electrodeposition, characterization and photoactivity of stoichiometric copper indium gallium diselenide (CIGS) thin films for solar cells. Herein we report the one-pot electrodeposition of copper indium gallium diselenide, CuIn(1-x)Ga(x)Se(2) (CIGS), thin films as the p-type semiconductor in an ionic liquid medium consisting of choline chloride/urea eutectic mixture known as Reline....

Busila, V.T.; Bacila, E.; Rosiu, L.; Topciu, V.; Barbulescu, L.; Damian, I., 1956: Contribution to the epidemiology of Q fever. Studii Si Cercetari de Inframicrobiologie 7(3-4): 295-301

Bai, J.; Hsu, L., 2013: Pain status and sedation level in Chinese children after cardiac surgery: an observational study. This study explored current pain status, sedation level and their trajectories in Chinese children after cardiac surgery. Pain and sedation management are fundamental care practices in the critical care setting, yet they both are frequently under-...

Miller, J.R., 1975: Intermolecular electron transfer by quantum mechanical tunneling. The transfer of electrons from one molecule to another by quantum mechanical tunneling has recently been implicated in biological electron transport. This report describes observations of electron transfer between aromatic molecules in a rigid mat...

Dean, L.A., 1962: Applications of radioisotopes to the study of fertilizer usage A critique. During 1947-1961 in the United States alone approximately 1000 field and greenhouse experiments of the following types were conducted with labelled fertilizers: the efficiency of fertilizer applications, comparison of fertilizer materials and prep...

Cole, R.N.; Hart, G.W., 1994: A multitude of synaptosomal proteins possess O-linked N-acetylglucosamine. Society for Neuroscience Abstracts 20(1-2): 1118

Dubin, B.A.; Bronson, D.M.; Eng, A.M., 1990: Acute hemorrhagic edema of childhood: an unusual variant of leukocytoclastic vasculitis. A case of acute hemorrhagic edema in a 3-year-old boy is presented. Its cause, differential diagnosis, and relation to Schönlein-Henoch purpura are discussed. Acute hemorrhagic edema is an unusual variant of leukocytoclastic vasculitis.