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

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.

Cyclopropylamines from N,N‐Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide

“…www.chemeurj.org [20][21][22][23][24][25][26][27][28], and with the use of more than one equivalent of 6, the achievable yields of the desired products are improved (Scheme 3).…”

“…[27,28] 3-Pyridyl ether derivatives such as 3-(pyrrolidin-2-ylmethoxy)pyridine, which corresponds to 69 (Scheme 12) without the spirocyclopropane moiety, have been found to exhibit subnanomolar affinities towards nAChRs. [29] Due to its influence on the basicity on the adjacent nitrogen, a spirocyclopropanated analogue such as 69 might have a modified activity.…”

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

“…99 DUB-165 (55) binds with K i value (0.051 nM) similar to that of UB-165 54 (0.04 nM), while the diazine analogues display lower affinity. Among them, the most potent compound was the 5-pyrimidinyl derivative 56a (K i 0.14 nM), which shows an affinity 76-and 142-fold higher for the a4b2 receptor than for the a7* or a3b4* subtypes, respectively, while the most selective was the 4-pyridazinyl analogue 56b…”

Guanidinium-based sulfonic acid as a new Brønsted acid organocatalyst in organic synthesis in water

“…It is important to note that the synthetic potentialities of MCRs with SO 3 H-functionalized Brønsted acid as environmentally benign and a recyclable catalyst have been combined to prepare quinoxalines [16] and pyrazines [17][18][19][20][21][22], which are seen in some important marketed drugs (I-III) [23][24][25], and urazole derivatives which also exhibit biological activities (IV-VII) [26][27][28][29] (Fig. 1).…”