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
  • 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: [email protected].
  • 4. Center for Drug Discovery, Georgetown University Medical Center, Research Building EP07, 3970 Reservoir Road, NW, Washington, DC 20057, United States. Electronic address: [email protected].
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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