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. Epub 2014 Apr 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Ligands
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Azetidines
  • Ligands
  • Pyridines
  • Receptors, Nicotinic
  • sazetidine-A