Synthesis and Nicotinic Binding Studies on Enantiopure Diazine Analogues of the Novel (2-Chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165

• Published in: Journal of medicinal chemistry 2002-02, Vol.45 (5), p.1064-1072
• Main Authors: Gohlke, Holger, Gündisch, Daniela, Schwarz, Simone, Seitz, Gunther, Tilotta, Maria Cristina, Wegge, Thomas
• Format: Article
• Language: English
• Subjects: Adrenal Glands - metabolism; Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Cholinergic system; In Vitro Techniques; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotinic Agonists - chemical synthesis; Nicotinic Agonists - chemistry; Nicotinic Agonists - pharmacology; Pharmacology. Drug treatments; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Stereoisomerism; Structure-Activity Relationship; Swine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010936y

As part of our program aimed at optimizing therapeutic effects over toxic effects (as observed in the naturally occurring nicotinic acetylcholine receptor modulators (−)-nicotine, (−)-epibatidine, (−)-ferruginine, and (+)-anatoxin-a), we investigated the bioisosteric potential of diazines in the field of (+)-anatoxin-a-type structures. In the series of diazine analogues of deschloro-UB-165 (DUB-165, 6), bioisosteric replacement of the 3-pyridyl pharmacophoric element by a 4-pyridazinyl, 5-pyrimidinyl, or 2-pyrazinyl moiety resulted in novel nAChR ligands 7, 8, and 9. A palladium-catalyzed Suzuki cross-coupling of the 3-diethylboranylpyridine (14) and a Stille cross-coupling of the corresponding tributylstannyl diazines 15 − 17 with the vinyl triflate 13 of the N-protected 9-azabicyclo[4.2.1]nonan-2-one 12 constitute the key steps in the syntheses of these enantiopure anatoxinoids 6 − 9. Studies of the in vitro affinity for (α4)2(β2)3, α3β4*, and α7* nAChR subtypes by radioligand binding assays demonstrated that the diazine analogues 7 − 9 can be considered as pharmacologically attractive bioisosteres of DUB-165 (6) but with different effects on the binding affinity with regard to the diazine moiety. The pyrimidine-containing bioisostere 8 turned out to be the most active diazine analogue, which interacts potently (K i = 0.14 nM) with the (α4)2(β2)3 subtype and differentiates significantly among the nAChR subtypes investigated. The nitrogens in this anatoxinoid 8 show by far the most negative atomic charges (calculated using the AM1 Hamiltonian). This qualitatively correlates with the highest binding affinity observed for 8 for all subtypes under consideration.