title: Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380.
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.
authors.affiliation: Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK. mogg_adrian@lilly.com
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mogg
authors.forename: Francis A
authors.initials: FA
authors.lastname: Jones
authors.forename: Ian A
authors.initials: IA
authors.lastname: Pullar
authors.forename: Christopher G V
authors.initials: CG
authors.lastname: Sharples
authors.forename: Susan
authors.initials: S
authors.lastname: Wonnacott
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005470:Fluorometry; D007202:Indicators and Reagents; D051379:Mice; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine; D001384:Azetidines; D007202:Indicators and Reagents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D017661:Receptors, Presynaptic; D000109:Acetylcholine; D002118:Calcium; D004298:Dopamine; D009638:Norepinephrine