Vol. 280, Issue 1, 373-383, 1997

Pharmacological Characterization of SIB-1765F: A Novel Cholinergic Ion Channel Agonist

Aida I. Sacaan, Richard T. Reid, Emily M. Santori, Pamala Adams, Lucia D. Correa, Lorrence S. Mahaffy, Leo Bleicher, Nicholas D. P. Cosford, Kenneth A. Stauderman, Ian A. McDonald, Tadimeti S. Rao and G. Kenneth Lloyd

SIBIA Neurosciences, Inc., La Jolla, California

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]--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 DHE. 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 h42 NAChR relative to h44 NAChRs in displacing [³H]-epibatidine binding and increasing cytosolic Ca⁺⁺ concentration in cell lines stably expressing h42 or h44.