Synthesis and evaluation of diazine containing bioisosteres of (-)-ferruginine as ligands for nicotinic acetylcholine receptors.
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.
Gündisch
D
D
Department of Pharmaceutical Chemistry, Rhein. Friedr.-Wilhelm-University, Kreuzbergweg 26, D-53115, Bonn, Germany.
Harms
K
K
Schwarz
S
S
Seitz
G
G
Stubbs
M T
MT
Wegge
T
T
D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002855:Chromatography, Thin Layer; D018360:Crystallography, X-Ray; D000087522:Cyanobacteria Toxins; D008024:Ligands; D008387:Marine Toxins / Q000737:chemistry / Q000494:pharmacology; D008698:Mesylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052998:Microcystins; D008968:Molecular Conformation; D015394:Molecular Structure; D009538:Nicotine / Q000737:chemistry / Q000494:pharmacology; D009947:Organotin Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014753:Vinyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001427:Bacterial Toxins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000087522:Cyanobacteria Toxins; D008024:Ligands; D008387:Marine Toxins; D008698:Mesylates; D052998:Microcystins; D009947:Organotin Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D014326:Tropanes; D014753:Vinyl Compounds; C418212:ferruginine; C437735:vinyl triflate; D010165:Palladium; D009538:Nicotine; C082748:epibatidine