1. Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380.
- Author
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Mogg AJ, Jones FA, Pullar IA, Sharples CG, and Wonnacott S
- Subjects
- Acetylcholine metabolism, Animals, Binding, Competitive drug effects, Calcium metabolism, Cell Line, Dopamine metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Fluorometry, Indicators and Reagents, Mice, Neostriatum drug effects, Neostriatum metabolism, Nicotinic Antagonists metabolism, Nicotinic Antagonists pharmacology, Norepinephrine metabolism, Radioligand Assay, Rats, Rats, Sprague-Dawley, Synaptosomes drug effects, Synaptosomes metabolism, Azetidines pharmacology, Nicotinic Agonists pharmacology, Pyridines pharmacology, Receptors, Nicotinic drug effects, Receptors, Presynaptic drug effects
- Abstract
The novel compound 5-iodo-A-85380 binds with higher affinity to alpha4beta2* nicotinic acetylcholine receptors (nAChR), compared with other nAChR subtypes (Mukhin et al., 2000). In the present study, we have confirmed that in competition binding assays for three major nAChR subtypes, 5-iodo-A-85380 is 850 and 27,000-fold more potent at rat brain alpha4beta2* binding sites than at alpha3beta4 and alpha7 subtypes, respectively. In functional assays, 5-iodo-A-85380 potently activated (EC50 12-35 nM) both alpha-CTx-MII-sensitive and -insensitive components of [3H]dopamine release from rat striatal synaptosomes, corresponding to alpha6beta2* and alpha4beta2* nAChR, respectively. 5-Iodo-A-85380 was markedly less potent at eliciting [3H]ACh release from rat interpeduncular nucleus synaptosomes, [3H]noradrenaline release from rat hippocampal slices, and Ca2+ increases in a cell line expressing rat alpha3beta4 nAChR (EC50 = 5, 3.2, 1.6 microM, respectively). As predicted by ligand binding studies, 5-iodo-A-85380 is a more discriminating agonist than the parent compound epibatidine. However, it is not specific for alpha4beta2* nAChR as it also potently activates alpha6beta2* nAChR.
- Published
- 2004
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