title: Pharmacological characterization of SIB-1765F: a novel cholinergic ion channel agonist.
abstract: Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-alpha-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (-)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 microM, respectively. Such stimulation was sensitive to mecamylamine and DH beta E. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1765F was less efficacious than (-)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (-)-nicotine. Similar to (-)-nicotine and (+/-)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (-)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for h alpha 4 beta 2 NAChR relative to h alpha 4 beta 4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic CA+2 concentration in cell lines stably expressing h alpha 4 beta 2 or h alpha 4 beta 4.
authors.affiliation: SIBIA Neurosciences, Inc., La Jolla, California, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: R T
authors.initials: RT
authors.lastname: Reid
authors.forename: E M
authors.initials: EM
authors.lastname: Santori
authors.forename: P
authors.initials: P
authors.lastname: Adams
authors.forename: L D
authors.initials: LD
authors.lastname: Correa
authors.forename: L S
authors.initials: LS
authors.lastname: Mahaffy
authors.forename: L
authors.initials: L
authors.lastname: Bleicher
authors.forename: N D
authors.initials: ND
authors.lastname: Cosford
authors.forename: K A
authors.initials: KA
authors.lastname: Stauderman
authors.forename: I A
authors.initials: IA
authors.lastname: McDonald
authors.forename: T S
authors.initials: TS
authors.lastname: Rao
authors.forename: G K
authors.initials: GK
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D007473:Ion Channels / Q000819:agonists*; D008297:Male; D017551:Microdialysis; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D009833:Olfactory Pathways / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D007473:Ion Channels; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C100989:altinicline maleate; D002118:Calcium; D004298:Dopamine; D009638:Norepinephrine