Journal article
Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors.
- Spang JE Center for Radiopharmaceutical Science, Department of Radiology, Swiss Federal Institute of Technology Zürich, Clinic of Nuclear Medicine, University Hospital Zürich, Switzerland.
- Bertrand S
- Westera G
- Patt JT
- Schubiger PA
- Bertrand D
- 2000-07-25
Published in:
- Chemistry & biology. - 2000
Amino Acid Motifs
Animals
Binding Sites
Bridged Bicyclo Compounds, Heterocyclic
Dose-Response Relationship, Drug
Microinjections
Models, Chemical
Molecular Structure
Neurons
Nicotinic Agonists
Nicotinic Antagonists
Patch-Clamp Techniques
Protein Isoforms
Pyridines
Rats
Receptors, Nicotinic
Recombinant Fusion Proteins
Sequence Alignment
Stereoisomerism
Structure-Activity Relationship
Xenopus
English
BACKGROUND
Studies of ligand gated channels strongly rely on the availability of compounds that can activate or inhibit with high selectivity one set or a subset of defined receptors. The alkaloid epibatidine (EPB), originally isolated from the skin of an Ecuadorian poison frog, is a very specific agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We used EPB derivatives to investigate the pharmacophore of nAChR subtypes.
RESULTS
Optically pure enantiomers of EPB analogues were synthesised. Analogues were obtained altered in the aromatic part: the chlorine was eliminated and the relative position of the pyridyl nitrogen changed. Voltage clamp electrophysiology was performed with these compounds on neuronal nAChRs reconstituted in Xenopus oocytes. The EPB derivatives show different activities towards the various nAChR subtypes.
CONCLUSIONS
Small changes in the molecular structure of EPB produce marked changes in its capacity to activate the nAChRs. Subtype specificity can be obtained by changing the position of or by eliminating the pyridyl nitrogen.
Studies of ligand gated channels strongly rely on the availability of compounds that can activate or inhibit with high selectivity one set or a subset of defined receptors. The alkaloid epibatidine (EPB), originally isolated from the skin of an Ecuadorian poison frog, is a very specific agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We used EPB derivatives to investigate the pharmacophore of nAChR subtypes.
RESULTS
Optically pure enantiomers of EPB analogues were synthesised. Analogues were obtained altered in the aromatic part: the chlorine was eliminated and the relative position of the pyridyl nitrogen changed. Voltage clamp electrophysiology was performed with these compounds on neuronal nAChRs reconstituted in Xenopus oocytes. The EPB derivatives show different activities towards the various nAChR subtypes.
CONCLUSIONS
Small changes in the molecular structure of EPB produce marked changes in its capacity to activate the nAChRs. Subtype specificity can be obtained by changing the position of or by eliminating the pyridyl nitrogen.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/s1074-5521(00)00138-1
- PMID 10903939
- Persistent URL
- https://sonar.ch/global/documents/122410
Statistics
Document views: 51
File downloads: