We have developed one-step syntheses of halogenated derivatives of (-)-cytisine featuring a halogen substituent at positions 3, 5 or 3 and 5 of the 2-pyridone fragment, and prepared the novel bioisosteric thiocytisine by oxygen-sulphur exchange. The affinities of these pyridone-modified analogs of (-)-cytisine for (α4) 2 (β2) 3 and α7* nAChRs in rat forebrain membranes were determined by competition with (+/-)-[ 3 H]epibatidine and [ 3 H]MLA, respectively. The 3-halocytisines 7 possess subnanomolar affinities for (α4) 2 (β2) 3 nAChRs, higher than those found for (-)-cytisine as well as for the 5-halocytisines 8 and 3,5-dihalocytisines 6. In contrast to the parent alkaloid the 3-halogenated species display much a higher affinity for the α7* nAChR subtype. The most potent molecule was 3-bromocytisine (7b) with preferential selectivity (200-fold) for the (α4) 2 (β2) 3 subtype [K i =10 pM (α4β2) and 2.0 nM (α7*)]. Replacement of the lactam with a thiolactam pharmacophore to thiocytisine (12) resulted in a subnanomolar affinity for the (α4) 2 (β2) 3 nAChR subtype (K i =0.832 nM), but in a drastic decrease of affinity for the α7* subtype; thiocytisine (12) has a K i value of 4000 nM (α7*), giving a selectivity of 4800-fold for the neuronal (α4) 2 (β2) 3 -nAChR and thus displaying the best affinity-selectivity profile in the series under consideration.