ABT-089 [3-(2(S)-pyrrolidinylmethoxy)-2-methyl-pyridine]: An orally effective cholinergic channel modulator with potential once-a-day dosing and cardiovascular safety

Abstract

ABT-089 [3-(2(S)-pyrrolidinylmethoxy)-2-methylpyridine] is a cholinergic channel modulator (ChCM) that selectively affects the function of neuronal nicotine acetylcholine receptor (nAChR) subtypes, enhances cognitive performance and has neuroprotective activity. Previous reports indicate that, unlike the other nicotinic receptor ligands, ABT-418 and (-)- nicotine, ABT-089 exhibits a more complex profile, having agonist, partial agonist, and inhibitory activities depending on the putative nAChR subtype with which it interacts. This study provides safety and pharmacokinetic information that clearly differentiate ABT-089 from both (-)-nicotine and ABT-418. ABT-089 has a reduced activation of ganglionic nAChRs, resulting in a reduced propensity to elicit side effects at high doses. Studies using guinea pig ileum indicate that ABT-089, in contrast to (-)- nicotine and the muscarinic agonist,methacholine, has no detectable effects on smooth muscle contractility, suggesting low potential for interference with gastrointestinal mobility. ABT-089 is orally available (33–76% in rat, dog, and monkey) and preliminary formulation data indicates that once-a-day formulation is feasible. In contrast, ABT-418 and (-)-nicotine have poor oral bioavailability in dog and monkey (<5%) and moderate bioavailability in rat (27 and 19%, respectively). Prolonged administration of ABT-089 does not result in cardiovascular liability in dogs. ABT-089 may be a safe and effective ChCM for the potential once-a-day oral treatment of the cognitive impairments and neurodegenerative processes associated with disorders such as Alzheimer's disease. Drug Dev. Res. 41:31–43, 1997. © 1997 Wiley-Liss, Inc.