Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Bioorg Med Chem Lett. 2011 Jan 1;21(1):88-91. doi: 10.1016/j.bmcl.2010.11.070. Epub 2010 Nov 24.

Abstract

A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC(50) of 0.95 nM, while the tris-tertiary amine analog 19 had an IC(50) of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / pharmacology
  • Animals
  • Dopamine / metabolism*
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / chemistry*
  • Nicotinic Antagonists / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Rats
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism
  • Structure-Activity Relationship

Substances

  • Amines
  • Isoquinolines
  • Nicotinic Antagonists
  • Pyridines
  • Receptors, Nicotinic
  • Dopamine