a-84543 and cytisine

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

Topics: Administration, Oral; Alkaloids; Animals; Anti-Anxiety Agents; Azocines; Biological Availability; Bungarotoxins; Cell Line; Cognition; Dogs; Haplorhini; Humans; Hypothermia; Isoxazoles; Ligands; Maze Learning; Mice; Molecular Structure; Psychomotor Performance; Pyrrolidines; Quinolizines; Receptors, Nicotinic; Rubidium; Structure-Activity Relationship

Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

Topics: Alkaloids; Animals; Azocines; Binding, Competitive; Brain; Cell Line; Cell Membrane; Ethers; Ganglia; Humans; Molecular Structure; Neurons; Nicotinic Agonists; Pyridines; Quinolizines; Radioligand Assay; Rats; Receptors, Nicotinic; Structure-Activity Relationship; Tritium