Novel Tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine Derivatives: Synthesis and Binding Affinity at Neuronal Nicotinic Acetylcholine Receptor Subtypes

Bioorg Med Chem. 2010 Jun 15;18(12):4498-508. doi: 10.1016/j.bmc.2010.04.065. Epub 2010 Apr 27.

Abstract

A group of novel tricyclic Delta(2)-isoxazolines (4b, 5b, 7a-b, and 8a-b) and 3-oxo-isoxazolidines (6a-b and 9a-b), structurally related to cytisine or norferruginine, was prepared through 1,3-dipolar cycloadditions involving suitable olefins and bromonitrile oxide. The target compounds were assayed at alpha4beta2 and alpha7 neuronal acetylcholine receptors (nAChRs). The results of competition binding experiments indicated for the new derivatives a reduction of the affinity at the alpha4beta2 subtype in comparison with the reference molecules, coupled with an overall negligible affinity at the alpha7 subtype. The binding mode of the bromo-Delta(2)-isoxazolines 4b and 7b, which were the highest affinity ligands in the series (K(i)=0.92 and 0.75 microM, respectively), was analyzed by applying a recently developed model of the alpha4beta2 nAChRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemistry
  • Animals
  • Azocines / chemistry
  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / chemistry*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Ligands
  • Models, Molecular
  • Neurons / metabolism*
  • Protein Binding
  • Quinolizines / chemistry
  • Rats
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • 3-bromo-5-oxa-4,10-diazatricyclo(6.3.1.0(2,6))dodec-3-ene
  • 5-bromo-3-oxa-4,11-diazatricyclo(6.2.1.0(2,6))undec-4-ene
  • Alkaloids
  • Azocines
  • Bridged Bicyclo Compounds, Heterocyclic
  • Chrna7 protein, rat
  • Heterocyclic Compounds, 3-Ring
  • Isoxazoles
  • Ligands
  • Quinolizines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • ferruginine
  • nicotinic receptor alpha4beta2
  • cytisine