Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A

被引：4

作者：

Liu, Yong ^{[1
]}

Paige, Mike ^{[1
]}

Olson, Thao T. ^{[2
]}

Al-Muhtasib, Nour ^{[2
]}

Xie, Teresa ^{[2
]}

Hou, Shujie ^{[1
]}

White, Michael P. ^{[1
]}

Cordova, Antoinette ^{[1
]}

Guo, Jessica L. ^{[1
]}

Kellar, Kenneth J. ^{[2
]}

Xiao, Yingxian ^{[2
]}

Brown, Milton L. ^{[1
]}

机构：

[1] Georgetown Univ, Med Ctr, Ctr Drug Discovery, Washington, DC 20057 USA

[2] Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, Washington, DC 20057 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 13期

关键词：

Sazetidine A; nAChR alpha 4 beta 2; Nicotinic receptor; Click chemistry; Bioisostere; Biostere; Photoaffinity label; SUSTAINED-RELEASE BUPROPION; RANDOMIZED CONTROLLED-TRIAL; PARTIAL AGONIST; DESENSITIZING AGENT; SMOKING-CESSATION; ANALGESIC AGENT; ALPHA-4-BETA-2; POTENT; VARENICLINE; BINDING;

D O I：

10.1016/j.bmcl.2014.04.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its' bioisostere-the triazole via click chemistry, showed a high binding affinity to alpha 4 beta 2 subtype (K-1 = 1.3 nM) and better selectivity to the alpha 4 beta 2 subtype over alpha 3 beta 4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a 'long tail' side chain for alpha 4 beta 2 nAChR binding. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：2954 / 2956

页数：3

共 31 条

[31] Design, Synthesis and Discovery of Picomolar Selective α4β2 Nicotinic Acetylcholine Receptor Ligands
Yenugonda, Venkata M.
Xiao, Yingxian
Levin, Edward D.
Rezvani, Amir H.
Thao Tran
Al-Muhtasib, Nour
Sahibzada, Niaz
Xie, Teresa
Wells, Corinne
Slade, Susan
Johnson, Joshua E.
Dakshanamurthy, Sivanesan
Kong, Hye-Sik
Tomita, York
Liu, Yong
Paige, Mikell
Kellar, Kenneth J.
Brown, Milton L.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (21) : 8404 - 8421

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