(S)-3-METHYL-5-(1-METHYL-2-PYRROLIDINYL)ISOXAZOLE (ABT-418) - A NOVELCHOLINERGIC LIGAND WITH COGNITION-ENHANCING AND ANXIOLYTIC ACTIVITIES.2. IN-VIVO CHARACTERIZATION

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418), an isoxaz ole analog of (-)-nicotine, is a potent agonist at the alpha-4/beta-2 subtype of neuronal nicotinic acetylcholine receptor (nAChR) that exis ts in mammalian brain (Americ et al., 1994). Compared to (-)-nicotine, ABT 418 has reduced potency to interact with the subunit isoforms of nAChR found in sympathetic ganglia, and it does not compete for alpha- bungarotoxin binding sites in brain or at the neuromuscular junction. ABT 418 [minimum effective dose (MED), 0.062 mu mol/kg i.p.) was 10-fo ld more potent in improving retention of avoidance learning in normal mice than (-)-nicotine, whereas the (R)-enantiomer of ABT 418, A-81754 , was inactive. The memory-enhancing effect of ABT 418 was prevented b y the nAChR channel blocker, mecamylamine. In the elevated plus-maze m odel of anxiety, ABT 418(MED, 0.19 mu mol/kg i.p.) increased open-arm exploration in mice, as previously shown for (-)-nicotine (MED, 0.62 m u mol/kg i.p.). A-81754, did not have anxiolytic-like effects in this test. Unlike the classical anxiolytic, diazepam, ABT 418 did not impai r rotorod performance in the dose range where beneficial effects occur red. In rats, ABT 418 (MED, 0.002 mu mol/kg i.v.) was remarkably poten t in enhancing basal forebrain-elicited increases in cortical cerebral blood flow, whereas resting cerebral blood flow was unaffected. Free running cortical electroencephalography in rats was unaffected by ABT 418 at a,dose of 1.9 mu mol/kg i.p., whereas the same dose of (-)-nico tine caused cortical activation (decreased power in the 1-13 Hz range and increased power in the 25-50 Hz range). Whereas ABT 418 was approx imately 3-to 10-fold more potent than (-)-nicotine in memory enhanceme nt and anxiolytic test paradigms, the compound had less emetic liabili ty in dogs as compared to (-)-nicotine, and was less potent than (-)-n icotine in eliciting hypothermia, seizures, death and reduction of loc omotor activity in mice. The measured pharmacokinetic or brain disposi tion properties of ABT 418 in rats did not account for the observed en hancement in efficacy with reduced toxicity as compared to (-)-nicotin e. The potent cognitive-enhancing and anxiolytic properties obtained f or ABT 418 in animal models without eliciting significant side effects suggest that this ligand is a selective activator of cholinergic chan nel-mediated behaviors. Thus, ABT 418 may represent a novel, safe and effective treatment of the cognitive and emotional dysfunctions associ ated with Alzheimer's disease.