TY - JOUR T1 - Pharmacological Characterization of SIB-1765F: A Novel Cholinergic Ion Channel Agonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 373 LP - 383 VL - 280 IS - 1 AU - Aida I. Sacaan AU - Richard T. Reid AU - Emily M. Santori AU - Pamala Adams AU - Lucia D. Correa AU - Lorrence S. Mahaffy AU - Leo Bleicher AU - Nicholas D. P. Cosford AU - Kenneth A. Stauderman AU - Ian A. McDonald AU - Tadimeti S. Rao AU - G. Kenneth Lloyd Y1 - 1997/01/01 UR - http://jpet.aspetjournals.org/content/280/1/373.abstract N2 - 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]-α-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 μM, respectively. Such stimulation was sensitive to mecamylamine and DHβE. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivomicrodialysis. 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 hα4β2 NAChR relative to hα4β4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic Ca++ concentration in cell lines stably expressing hα4β2 or hα4β4. The American Society for Pharmacology and Experimental Therapeutics ER -