Cytisine very potently binds and activates the α3β4 and α7 nicotinic subtypes, but only partially agonises the α4β2 subtype. Although with a lower affinity than cytisine, new cytisine derivatives with different substituents on the basic nitrogen (CC1-CC8) bind to both the heteromeric and homomeric subtypes, with higher affinity for brain [3H]epibatidine receptors. The cytisine derivatives were tested on the Ca2+ flux of native or transfected cell lines expressing the rat α7, or human α3β4 or α4β2 subtypes using Ca2+ dynamics in conjunction with a fluorescent image plate reader. None elicited any response at doses of up to 30-100 μM, but all inhibited agonist-induced responses. Compounds CC5 and CC7 were also electrophysiologically tested on oocyte-expressed rat α4β2, α3β4 and α7 subtypes. CC5 competitively antagonised the α4β2 and α3β4 subtypes with similar potency, whereas CC7 only partially agonised them with maximum responses of respectively 3% and 11% of those of 1 mM acetylcholine. Neither compound induced any current in the oocyte-expressed α7 subtype, and both weakly inhibited acetylcholine-induced currents. Adding chemical groups of a different class or size to the basic nitrogen of cytisine leads to compounds that lose full agonist activity on the α3β4 and α7 subtypes.
|Titolo:||Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes.|
|Autori interni:||CLEMENTI, FRANCESCO (Penultimo)|
|Parole Chiave:||Agonist; Antagonist; Binding; Cytisine; Electrophysiology; FLIPR; Nicotinic receptor, neuronal; Partial agonist|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2003|
|Digital Object Identifier (DOI):||10.1016/S0014-2999(03)01817-X|
|Appare nelle tipologie:||01 - Articolo su periodico|