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Structural determinants of lolitrems for inhibition of BK large conductance Ca2+-activated K+ channels.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2009 Mar 01; Vol. 605 (1-3), pp. 36-45. Date of Electronic Publication: 2009 Jan 10. - Publication Year :
- 2009
-
Abstract
- Lolitrem B is an indole-diterpenoid neurotoxin which is the main causative agent of ryegrass staggers, an animal disease associated with tremors and incoordination. It is also a potent inhibitor of large conductance calcium-activated potassium (BK) channel activity (IC(50)=4 nM). Furthermore, we have recently shown that the motor function deficits induced by lolitrem B are specifically mediated by BK channels, making the toxin a valuable tool for investigating the molecular function and physiological roles of these channels. To determine what structural features of BK channel agents are required for high potency, the effect of lolitrem B and seven structurally-related lolitrems on BK channel activity has been measured. Concentration-responses and conductance-voltage (G-V) relationships were determined for each compound and related to the different structure types. This study has identified seven new BK channel inhibitors and has allowed the identification of two key structural features required for high potency BK channel activity by lolitrems.
- Subjects :
- Cell Line
Dose-Response Relationship, Drug
Humans
Indole Alkaloids
Inhibitory Concentration 50
Mycotoxins administration & dosage
Mycotoxins chemistry
Neurotoxins administration & dosage
Neurotoxins chemistry
Potassium Channel Blockers administration & dosage
Potassium Channel Blockers chemistry
Potassium Channel Blockers pharmacology
Structure-Activity Relationship
Large-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors
Mycotoxins pharmacology
Neurotoxins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 605
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 19210977
- Full Text :
- https://doi.org/10.1016/j.ejphar.2008.12.031