PHARMACOLOGICAL CHARACTERIZATION OF SIB-1765F - A NOVEL CHOLINERGIC ION-CHANNEL AGONIST

Nicotine, the prototypical agonist for neuronal nicotinic acetylcholin e receptors (NAChR), nonselectively activates NAChR limiting its use i n elucidating the function of NAChR subtypes. SIB-1765F is a subtype s elective NAChR agonist that displaces [H-3]-nicotine binding with an I C50 of 4.6 nM and [H-3]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [H-3]-QNB or [I- 125]-alpha-bungarotoxin. SIB-1765F did not inhibit human or rat cholin esterases or the uptake of [H-3]-DA in synaptosomal preparations. SIB- 1765F mimicked (-)-nicotine in stimulating [H-3]-DA release from rat s triatal and olfactory tubercle slices, with EC(50) values of 99.6 and 39.6 mu M, respectively. Such stimulation was sensitive to mecamylamin e and DH beta E. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1 765F was less efficacious than (-)-nicotine at stimulating [H-3]-NE re lease from rat hippocampal slices; in contrast, SIB-1765F increased [H -3]-NE release from rat thalamic and cortical slices with efficacies a pproaching those of (-)-nicotine. Similar to (-)-nicotine and (+/-)-ep ibatidine, subcutaneous administration of SIB-1765F increased the turn over rate of dopamine ex vivo both in the striatum and olfactory tuber cles in a mecamylamine-sensitive manner. Because the release of striat al DA and hippocampal NE appears to be regulated by distinct NAChR, di fferential effects of SIB-1765F on striatal DA and hippocampal NE rele ase 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 [H-3]-epibatidine binding and i ncreasing cytosolic Ca++ concentration in cell lines stably expressing h alpha 4 beta 2 or h alpha 4 beta 4.