In summary, the discovery a novel series of neuronal CCR ligands in which a substituted isoxazole ring has been incorporated as a bioisosteric replacement for the pyridine ring of nicotine is reported. Receptor binding studies show that this modification is favorable in both the (S)- and (R)-enantiomeric series to interact with the α4β2 subtype of neuronal CCR, the major receptor subtype with the (-)-nicotine binding site in brain.49,50 Remarkably beneficial cognitive enhancing and anxiolytic effects have also been produced in mice with 4a and 3b at dosage levels averaging 1 order of magnitude lower than those observed with 2a. Further in vitro62 characterization of 4a has indicated that it is a potent and selective agonist of some putative subtypes of neuronal CCRs. Moreover, 4a·HCl had less emetic liability in dogs compared to 2a and was less potent in eliciting seizures and death in mice.63 Ligands for neuronal CCRs possessing such a behavioral profile and with a more favorable therapeutic window with respect to nicotinically mediated adverse side effects may be useful in the treatment of AD related personality changes and memory loss. This novel series of isoxazole compounds represents an exciting new area of investigation where safe and effective ChCAs to treat CNS disorders involving loss of cholinergic function will continue to be explored.