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.
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 (alpha4)(2)(beta2)(3), alpha3(beta)4, and alpha7 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 (alpha4)(2)(beta2)(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.
Gohlke
Holger
H
Institut für Pharmazeutische Chemie der Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
Gündisch
Daniela
D
Schwarz
Simone
S
Seitz
Gunther
G
Tilotta
Maria Cristina
MC
Wegge
Thomas
T
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
C407663:(2-chloro-5-pyridyl)-9-azabicyclo(4.2.1)non-2-ene; C450155:2-(pyrimidin-5-yl)-9-azabicyclo(4.2.1)non-2-ene; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D008024:Ligands; D018722:Nicotinic Agonists; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011978:Receptors, Nicotinic