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[3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2 .1]heptane], a novel high-affinity alpha7 neuronal nicotinic receptor agonist: radioligand binding characterization to rat and human brain

Anderson, David J.
Bunnelle, William
Surber, Bruce
Du, Jia
Surowy, Carol
Marguerat, Anouk
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Published in The Journal of pharmacology and experimental therapeutics. 2008, vol. 324, no. 1, p. 179-187
Abstract Receptor binding was characterized for [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicycl o[2.2.1]heptane ([(3)H]A-585539), a selective high-affinity alpha7 nicotinic acetylcholine receptor (nAChR) agonist with rapid kinetics, low nonspecific binding, and high specific activity. At 4 degrees C, the association was monophasic and rapid (t((1/2)) = 8.0 min); dissociation was slower (t((1/2)) = 64.2 min). The K(d) in rat brain at 4 degrees C was 0.063 nM, whereas at 22 and 37 degrees C, the K(d) values were 0.188 and 0.95 nM, respectively. In contrast, the B(max) (34 fmol/mg protein) was unaffected by temperature. In human cortex, [(3)H]A-585539 bound with a K(d) of 0.066 nM and a B(max) of 5.8 fmol/mg protein at 4 degrees C, whereas under similar conditions, specific [(3)H]methyllycaconitine ([(3)H]MLA) binding was not measurable. A number of agonist and antagonist nAChR ligands displaced binding to rat brain membranes with rank order of affinity similar to that for [(3)H]MLA, and in general, a 5 to 10-fold higher affinity was observed for [(3)H]A-585539 binding. There was also a good correlation of K(i) values between [(3)H]A-585539 binding to rat brain and human cortex. The use of a alpha7/5-hydroxytryptamine type-3 chimera revealed that the N-terminal domain of alpha7 nAChR was sufficient to faithfully reproduce the pharmacology of [(3)H]A-585539 binding. Autoradiographic studies comparing [(3)H]A-585539 and [(125)I]alpha-bungarotoxin revealed a similar pattern of labeling in the rat. In summary, [(3)H]A-585539 was shown to have excellent binding characteristics in rat and human brain and represents the first high-affinity alpha7 agonist radioligand with utility in the characterization of this important nAChR subtype that is targeted toward ameliorating cognitive deficits underlying neuropsychiatric and neurodegenerative disorders.
Keywords Aconitine/analogs & derivatives/metabolismAnimalsBenzamides/metabolismBicyclo Compounds/metabolismBicyclo Compounds, Heterocyclic/*metabolismBrain/*metabolismBridged Compounds/metabolismBungarotoxins/metabolismCell LineHumansNicotine/metabolismNicotinic Agonists/*metabolismNicotinic Antagonists/metabolismPyridazines/*metabolismRadioligand AssayRatsRats, Sprague-DawleyReceptors, Nicotinic/*metabolismSpiro Compounds/metabolism
PMID: 17959745
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ANDERSON, David J. et al. [3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2 .1]heptane], a novel high-affinity alpha7 neuronal nicotinic receptor agonist: radioligand binding characterization to rat and human brain. In: The Journal of pharmacology and experimental therapeutics, 2008, vol. 324, n° 1, p. 179-187. doi: 10.1124/jpet.107.130062 https://archive-ouverte.unige.ch/unige:19154

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Deposited on : 2012-03-27

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