Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists

Bioorg Med Chem. 2006 Dec 15;14(24):8219-48. doi: 10.1016/j.bmc.2006.09.019. Epub 2006 Oct 2.

Abstract

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Bungarotoxins
  • Cells, Cultured
  • Drug Design*
  • Electrophysiology
  • Evoked Potentials, Auditory / drug effects
  • Hippocampus / drug effects
  • Ion Channel Gating / drug effects
  • Molecular Structure
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Nicotinic / chemistry*
  • Structure-Activity Relationship
  • Synapses / drug effects
  • Synapses / physiology
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Bungarotoxins
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor