The current project examined the ability of a novel series of guandine and amidine-containing nicotine analogs to interact with several native and recombinantlyexpressed mammalian neuronal nicotinic-acetylcholine receptor (nAChR) subtypes. Rational drug design methods and parallel organic synthesis was used to generate a library of guanidine-containing nicotine (NIC) analogs (AH compounds). A smaller series of amidine-containing nicotine analogs (JC compounds) were also synthesized. In total, >150 compounds were examined. Compounds were first assayed for affinity in a high-throughput [3H]epibatidine radioligand-binding screen. Lead compounds were evaluated in subtype-selective binding experiments to probe for affinity at the α4β2* and α7* neuronal nAChRs. Several compounds were identified which possess affinity and selectivity for the α4β2* subtype [AH-132 (Ki=27nm) and JC-3-9 (Ki=11nM)]. Schild analysis of binding suggests a complex one-site binding interaction at the desensitized high-affinity nAChR. Whole-cell functional fluorescence (FLIPR) assays revealed mixed subtype pharmacology. AH-compounds were identified which act as activators and inhibitors at nAChR subtypes, while lead JC-compounds were found which possess full agonist activity at α4β2* and α3β4* subtypes. Compounds were identified as partial agonists, full agonists and inhibitors of multiple nAChR subtypes. Several SAR-based, ligand-receptor pharmacophore models were developed to guide future ligand design. Second-generation lead compounds were identified.