ABT — 418, a Novel Nicotinic Agonist

Abstract

With the plethora of receptor targets evolving as the result of nicotinic acetylcholine receptor (nAChR) cloning it is possible that new molecular entities selective for subtypes of nAChRs can be developed which are potentially free of the side effect liabilities associated with (-)-nicotine. Recent data also suggests that neuronal nAChR function can be enhanced at sites distinct from where (-)-nicotine interacts on the a subunit. nAChR agonists whose actions may occur via the selective interaction with central nAChRs subtypes, and allosteric modulators that indirectly affect ligand-gated nAChR function encompass a broader class of compounds which can be termed cholinergic channel activators (ChCAs). Functionally, ChCAs may enhance central neuronal nAChR mediated transmission while substantially reducing the side-effect liabilities normally associated with (-)-nicotine. ChCAs lacking cardiovascular or other CNS side effects associated with (-)-nicotine may thus represent a potential novel therapeutic approach to ameliorate many of the CNS deficits accompanying AD or other related disorders. ABT 418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole hydrochloride] is a selective prototypic ChCA currently in development for the treatment of AD (see accompanying abstracts). ABT-418 may be a safe and effective ChCA for the potential treatment of the cognitive and emotional impairments associated with AD. The therapeutic potential of ChCAs for neuroprotection, smoking cessation, anxiety disorders, schizophrenia, attentional deficit disorder, Touretté s syndrome, analgesia and depression will be reviewed.