ferruginine and vinyl-triflate

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 alpha4beta2 and remarkably low affinity for the alpha7* nAChR subtypes. Among the compounds synthesized and tested, 7 was the most active one with K(i)=3.7 nM (alpha4beta2). Compared with the lead 3, this value represents a 30-fold improvement in the affinity for the alpha4beta2 subtype combined with a substantially improved selectivity ratio between the alpha4beta2 and alpha7* subtypes.

Topics: Animals; Bacterial Toxins; Brain; Bridged Bicyclo Compounds, Heterocyclic; Catalysis; Chromatography, Thin Layer; Crystallography, X-Ray; Cyanobacteria Toxins; Ligands; Marine Toxins; Mesylates; Microcystins; Molecular Conformation; Molecular Structure; Nicotine; Organotin Compounds; Palladium; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Spectrophotometry, Ultraviolet; Stereoisomerism; Structure-Activity Relationship; Tropanes; Vinyl Compounds