Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors
Je. Spang et al., Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors, CHEM BIOL, 7(7), 2000, pp. 545-555
Background: Studies of ligand gated channels strongly rely on the availabil
ity of compounds that can activate or inhibit with high selectivity one set
or a subset of defined receptors. The alkaloid epibatidine (EPB), original
ly isolated from the skin of an Ecuadorian poison frog, is a very specific
agonist for the neuronal nicotinic acetylcholine receptors (nAChRs). We use
d EPB derivatives to investigate the pharmacophore of nAChR subtypes.
Results: Optically pure enantiomers of EPB analogues were synthesised. Anal
ogues were obtained altered in the aromatic part: the chlorine was eliminat
ed and the relative position of the pyridyl nitrogen changed. Voltage clamp
electrophysiology was performed with these compounds on neuronal nAChRs re
constituted in Xenopus oocytes. The EPB derivatives show different activiti
es 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 nitroge
n.