[Abstract Title]. - Society for Neuroscience

Disclosures: A.J. Hone , None; Y. Xiao, None; S. Christensen, None; D. Yoshikami,
None; J.M. McIntosh, None.
Poster
233. Nicotinic Aacetylcholine Receptors: Regulation and Function II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 233.17/C19
Topic: B.02.a. Nicotinic acetylcholine receptors in brain: Physiology and function
Support: The Royal Society
Title: Effects of nitrated cytisine on α4β2 and α7 receptors
Authors: *A. L. CARBONE 1 , P. SÁEZ-BRIONES 3 , M. REBOLLEDO-FUENTES 4 , G.
ZAPATA-TORRES 4 , G.-H. MANUEL 4 , M. MORONI 2 , B. K. CASSELS 4 , I. BERMUDEZ 2 ;
1 Sch. of Life Sci., 2 Oxford Brookes Univ., Oxford, United Kingdom; 3 Univ. de Santiago de
Chile, Santiago, Chile; 4 Univ. de Chile, Santiago, Chile
Abstract: Cytisine, an alkaloid of the quinolizidine family, is a potent agonist at α4β2 and α7
nicotinic acetylcholine receptors (nAChR). Halogen substituents on position C(3) or C(5) bring
about remarkable changes in the radioligand binding affinity and functional potency and efficacy
of cytisine. In the present study, we have nitrated cytisine at position C(3) or C(5) and
determined the pharmacological consequences of the nitration on α4β2 and α7 using a
combination of binding, functional and molecular modeling approaches. Radioligand binding
assays showed that 3-NO2cytisine induces an increase in affinity at α4β2 and α7 receptors,
whilst 5-NO2-cytisine causes a significant increase in binding affinity at both receptor types.
Functional studies on receptors expressed heterologously in Xenopus laevis oocytes revealed that
3-NO2-cytisine behaves as a low efficacy partial agonist of both high and low sensitivity α4β2
receptors and as a full agonist of low potency at a7 receptors. In contrast, neither α4β2 nor α7
nAChR are activated by 5-NO2-cytisine. Docking experiments revealed that 3-NO2-cytisine
may adopt different orientations inside the binding site at α7 but not at α4β2 receptors, compared
to cytisine. These studies also revealed that position C(5) of cytisine points towards charged side
chains, which may underlie the loss of agonist activity observed for 5-NO2-cytisine. Our
findings are in agreement with the existence of different structural requirements at each receptor
subtype associated to affinity, functional potency and efficacy.
Disclosures: A.L. Carbone , None; P. Sáez-Briones, None; M. Rebolledo-Fuentes, None; G.
Zapata-Torres, None; G. Manuel, None; M. Moroni, None; B.K. Cassels, None; I.
Bermudez, None.