Chemical modification of epibatidine causes a switch from agonist to antagonist and modifies its selectivity for neuronal nicotinic acetylcholine receptors

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.