4-Phenoxybutoxy-substituted heterocycles--a structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3.
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.
Bodendiek
Silke B
SB
Department of Pharmacology, University of California, Davis, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616, USA.
Mahieux
Cédrick
C
Hänsel
Wolfram
W
Wulff
Heike
H
D000078223:5-Methoxypsoralen; D001327:Autoimmune Diseases / Q000188:drug therapy; D005363:Ficusin / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects; D008730:Methoxsalen / Q000031:analogs & derivatives; D000073718:Pancreatitis-Associated Proteins; D032105:Ruta; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology
D006571:Heterocyclic Compounds; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D000078223:5-Methoxypsoralen; D005363:Ficusin; D008730:Methoxsalen