Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies

A series of hitherto unknown enantiopure (-)-ferruginine analogues of type 8 and 9 was prepared and tested for the affinity toward the nicotinic acetylcholine receptor (nAChR) subtypes (alpha4)2(beta2)3, alpha7*, alpha3beta4*, and (alpha1)2beta1gamma delta. The stereoconservative asymmetric syntheses started with (-)-cocainhydrochloride (10) from the chiral pool which was transformed into the chiral building blocks (+)-2-tropanone (11) and to (-)-anhydroecgonine (18). Key steps of the syntheses are novel extensions to existing methodology e.g. a Suzuki Pd(0)-mediated cross-coupling of vinyl triflate (12) with the heteroaryl organoboranes 13-15 and an inverse type [4+2]-cycloaddition with 1,2,4,5-tetrazine (21). The bioisosteric replacement of the 3-acetyl pharmacophoric element of the lead 6 by a 3-pyridyl, 5-chloropyridyl, 5-pyrimidinyl, 2-pyrazinyl, or 4-pyridazinyl moiety resulted in nAChR ligands with Ki-values ranging from 1.1-713 nM toward the (alpha4)2(beta2)3 subtype combined with significant differentiation among the nAChR subtypes when tested in vitro by radioligand binding studies. Generally the ferrugininoids are less potent than the corresponding norferrugininoids. Similar to results of the norferrugininoid series the novel azine substituted ferrugininoids 8 proved to be more potent than the diazine analogues 9; both exhibited higher affinities compared to the lead 6. The 5-chloropyridyl-containing variant 8b [1R, 5S)-enantiomer] turned out to be the most active nAChR ligand with a 12-fold higher affinity toward the (alpha4)2(beta2)3 subtype than the corresponding (1S, 5R)-form ent-8b.