Identification of novel (isoxazole)methylene-1-azabicyclic compounds with high affinity for the central nicotinic cholinergic receptor

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Abstract

A novel class of compounds with high affinity (IC50 = 3.4 – 500 nM) for the central nicotinic cholinergic receptor was synthesized. The compounds were characterized in vitro and in vivo and compared to ABT 418 and nicotine. The new ligands are effective nicotinic compounds with biological profiles distinguishable from reference compounds.

A novel class of compounds with high affinity (IC50 = 3.4–500 nM) for the central nicotinic cholinergic receptor was synthesized. The compounds were characterized in vitro and in vivo and compared to ABT 418 and nicotine. The new ligands are effective nicotinic compounds with biological profiles distinguishable from reference compounds.

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    left panel). NNC 90-0270 caused a maximum of 60% nicotine appropriate responding (Olesen et al., 1997; ED50: 0.1 mg/kg), the nicotinic receptor agonist lobeline (Decker et al., 1993) caused a maximum of 40% nicotine appropriate responding (Olesen et al., 1998: ED50: > 6 mg/kg), and the AChR ligand [(S)-3-methyl-5-(1- methyl-2-pyrrolidinyl)isoxazole hydrochloride] (ABT-418; Brioni et al., 1995) a maximum of 72% nicotine appropriate responding (Olesen et al., 1997: ED50: 0.2 mg/kg), as shown in Fig. 5, left panel. Nicotine and cytisine did not reduce response rates at the doses tested, whereas NNC 90-0270, lobeline and ABT-418 all produced dose-dependent response rate decreases (Fig. 5, right panel), suggesting that active dose ranges had been achieved.

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    All compounds a and c were obtained and tested as racemic mixtures, and 8b was tested as a (Z/E)-mixture. The ability of the compounds to displace the nicotinic agonist [3H]methylcarbamylcholine (MCC) from native cholinergic binding sites in rat brain cortex was determined as previously described (Tables 1 and 2).6,11,12 All the compounds, except (Z/E)-8b and (Z)-6b, bound to the nicotinic binding site with moderate to high affinity.

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