title: Pharmacophore modeling for hERG channel facilitation.
abstract: Human ether-a-go-go-related gene (hERG) channels play a critical role in cardiac action potential repolarization. The unintended block of hERG channels by compounds can prolong the cardiac action potential duration and induce arrhythmia. Several compounds not only block hERG channels but also enhance channel activation after the application of a depolarizing voltage step. This is referred to as facilitation. In this study, we tried to extract the property of compounds that induce hERG channel facilitation. We first examined the facilitation effects of structurally diverse hERG channel blockers in Xenopus oocytes. Ten of 13 assayed compounds allowed facilitation, suggesting that it is an effect common to most hERG channel blockers. We constructed a pharmacophore model for hERG channel facilitation. The model consisted of one positively ionizable feature and three hydrophobic features. Verification experiments suggest that the model well describes the structure-activity relationship for facilitation. Comparison of the pharmacophore for facilitation with that for hERG channel block showed that the spatial arrangement of features is clearly different. It is therefore conceivable that two different interactions of a compound with hERG channels exert two pharmacological effects, block and facilitation.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Furutani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inanobe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ohno
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000818:Animals; D001262:Atenolol / Q000737:chemistry / Q000494:pharmacology; D002744:Chlorpheniramine / Q000737:chemistry / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D005473:Fluoxetine / Q000737:chemistry / Q000494:pharmacology; D006220:Haloperidol / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007099:Imipramine / Q000737:chemistry / Q000494:pharmacology; D008790:Metoprolol / Q000737:chemistry / Q000494:pharmacology; D009661:Nortriptyline / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D011398:Promethazine / Q000737:chemistry / Q000494:pharmacology; D011433:Propranolol / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013015:Sotalol / Q000737:chemistry / Q000494:pharmacology; D016593:Terfenadine / Q000737:chemistry / Q000494:pharmacology; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D005473:Fluoxetine; D002744:Chlorpheniramine; D001262:Atenolol; D016593:Terfenadine; D011433:Propranolol; D013015:Sotalol; D009661:Nortriptyline; D014700:Verapamil; D011398:Promethazine; D008790:Metoprolol; D006220:Haloperidol; D007099:Imipramine