Neuronal nicotinic acetylcholine receptors (nAChRs) form a family of ACh-gated cation channels made up of different subtypes. They are widely distributed in peripheral and central nervous systems and are involved in complex cerebral processes as learning, memory, nociception, movement, etc. The possibility that subtype-selective ligands be used in the treatment of CNS disorders promoted the synthesis of a large number of structural analogues of nicotine and epibatidine, two very potent nAChR agonists. Pursuing our long standing research on the structural modification of quinolizidine alkaloids, we devoted our attention to cytisine, another very potent ligand for many nAChR subtypes. Thus a systematic structural modification of cytisine was undertaken in order to obtain compounds of potential therapeutic interest at peripheral as well as central level, with a particular concern for achieving nAChR subtype selective ligands. Up to the present more than 80 cytisine derivatives, mainly of N-substitution and a few by modifying the pyridone ring, have been prepared. The biological results, which concern so far about an half of the prepared compounds, indicate that the introduction of a nitro group in position 3 of the pyridone nucleus further enhances the high affinity of cytisine, while the introduction of substituents on the basic nitrogen, though reducing in different degrees the affinity, gives rise to compounds with a higher selectivity for central (alpha(4)beta(2)) versus gangliar (alpha(3)-containing) receptor subtype. On the other hand, the analgesic, antihypertensive and inotropic activities found in some N-substituted cytisines, represent an attractive starting point for the development of more active compounds.