2. Academic Validation
  3. Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A

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

  • Bioorg Med Chem Lett. 2014 Jul 1;24(13):2954-6. doi: 10.1016/j.bmcl.2014.04.036.
Yong Liu 1,  Mikell Paige 1,  Thao T Olson 2,  Nour Al-Muhtasib 2,  Teresa Xie 2,  Shujie Hou 1,  Michael P White 1,  Antoinette Cordova 1,  Jessica L Guo 1,  Kenneth J Kellar 2,  Yingxian Xiao 3,  Milton L Brown 4
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
  • 2 Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States.
  • 3 Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington, DC 20057, United States. Electronic address: yxiao02@georgetown.edu.
  • 4 Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States. Electronic address: mb544@georgetown.edu.
PMID: 24844195 DOI: 10.1016/j.bmcl.2014.04.036
Abstract

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 α4β2 subtype (Ki=1.3 nM) and better selectivity to the α4β2 subtype over α3β4 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 α4β2 nAChR binding.

Keywords

Bioisostere; Biostere; Click chemistry; Nicotinic receptor; Photoaffinity label; Sazetidine A; nAChR α4β2.

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