Syntheses and evaluation of pyridazine and pyrimidine containing bioisosteres of (+/-)-pyrido[3.4-b]homotropane and pyrido-[3.4-b]tropane as novel nAChR ligands.
Bioisosteric replacement of the pyridine pharmacophoric element in (+/-)-pyrido[3.4-b]homotropane (PHT) and pyrido[3.4-b]tropane with the pyridazine and pyrimidine nucleus resulted in hitherto unknown nAChR ligands such as 5-8. Inverse type Diels-Alder reactions constitute the key steps in the new routes to the pyridazine- or pyrimidine-annulated bioisosteres. The enantiopure (+)-2-tropinone (11) from the 'chiral pool' is transformed to the ring-expanded silyl enol ether 12 and to the enamine 15. Both proved to be highly dienophilic species in the inverse type [4+2] cycloaddition reactions with the 1,2,4,5-tetrazines 13 and 16a,b or with the 1,3,5-triazine 19 to provide the enantiopure target compounds 5-7. In the same way the racemic pyrimidine-annulated species 8 was obtained from 3-tropanone 21. The new ligands were tested for their in vitro affinity for (alpha4)2(beta2)3 and alpha7* nAChR subtype. In comparison to PHT, well known to exhibit affinity for agonist binding sites in rat brain approximately equivalent to that of (+)-anatoxin-a (1), replacement of the pyridine by the bioisosteric pyridazine resulted in 30-fold lower affinity at the (alpha4)2(beta2)3 subtype. The annulated diazinotropanes 6-8, ligands with ferruginine-like structures more or less retained the affinity of (-)-norferruginine (3) except of compound 7. Remarkably, all of the novel ligands are devoid of affinity at the alpha7* subtype.
Gündisch
Daniela
D
Department of Pharmaceutical Chemistry, Rhein.Friedr.Wilh. University, Kreuzbergweg 26, D-53115, Bonn, Germany.
Kämpchen
Thomas
T
Schwarz
Simone
S
Seitz
Gunther
G
Siegl
Johanna
J
Wegge
Thomas
T
D008024:Ligands; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013057:Spectrum Analysis; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011978:Receptors, Nicotinic; D014326:Tropanes; C055134:pyrido(3,4-b)norhomotropane; C062482:pyridazine; C030986:pyrimidine