Synthesis and evaluation of diazine containing bioisosteres of (−)-ferruginine as ligands for nicotinic acetylcholine receptors Original Research Article

In this structure–affinity relationship (SAFIR) study, the bioisosteric potential of diazines in the field of ferruginine-type nAChR ligands was investigated. Novel enantiopure analogues of (−)-Ferruginine (3) such as 6–8 were synthesized utilizing enantiomerically pure N-protected (+)-2-tropanone 9 from the ‘chiral pool’ as versatile chiral building block and a palladium-catalyzed Stille cross-coupling of the tributylstannyl diazines 12, 14 and 16 with the vinyl triflate 11 of (+)-2-tropanone 9. The structures of the novel diazine analogues 6–8 of (−)-ferruginine (3) were assigned on the basis of spectral data, that of ligand 7 being additionally verified by X-ray crystallography. The bioisosteric replacement of the acetyl moiety as structural part of the lead compound 3 with the pyridazine, pyrimidine and pyrazine nucleus resulted in ligands with high to moderate affinity for the central α4β2 and remarkably low affinity for the α7* nAChR subtypes. Among the compounds synthesized and tested, 7 was the most active one with Ki=3.7 nM (α4β2). Compared with the lead 3, this value represents a 30-fold improvement in the affinity for the α4β2 subtype combined with a substantially improved selectivity ratio between the α4β2 and α7* subtypes.