Home
Resources
Publications
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

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

Holger Gohlke, Daniela Gündisch, Simone Schwarz, Gunther Seitz, Maria Cristina Tilotta, Thomas Wegge

J Med Chem. 2002 Feb 28;45(5):1064-72.

PMID: 11855986

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP153435633	2-(Tributylstannyl)pyrimidine		153435-63-3	Price
AP155191687	2-Chloro-5-(tributylstannyl)pyrimidine		155191-68-7	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: