Recent studies have shown that neuronal nicotinic acetylcholine receptors (nAChRs) modulate neurotransmitter release and their deficit in Alzheimer's disease (AD) makes subtype-selective nAChR agonists potential therapeutics. As part of a program to identify selective nAChR agonists that stimulate acetylcholine release from the hippocampus and cortex, we report the synthesis and pharmacological evaluation of 4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a novel selective agonist of human neuronal nAChRs. Compared with other nicotinic agonists (e.g., ABT-418, ABT-089, GTS-21), SIB-1553A markedly increases acetylcholine levels in the hippocampus and cortex. Pharmacological evaluation in HEK cells and Xenopus oocytes confirmed its selectivity for β4-containing nAChR subtypes. SIB-1553A efficiently releases neurotransmitters in vitro and in vivo, and in behavioral tests, it reverses the working memory deficits of aged C57BL/6 mice, with the racemate being more active than either enantiomer. These data suggest that SIB-1553A is a novel nAChR agonist with therapeutic potential for the symptomatic treatment of Alzheimer's disease and other cognitive disorders.