Conversion of a highly selective sigma-1 receptor-ligand to sigma-2 receptor preferring ligands with anticocaine activity

J Med Chem. 2008 Mar 13;51(5):1482-6. doi: 10.1021/jm701357m. Epub 2008 Feb 16.

Abstract

Cocaine's toxicity can be mitigated by blocking its interaction with sigma-1 receptors. The involvement of sigma-2 receptors remains unclear. To investigate their potential role, we have designed compounds through a convergent synthesis utilizing a highly selective sigma-1 ligand and elements of a selective sigma-2 ligand. Among the synthesized compounds was produced a subnanomolar sigma-2 ligand with an 11-fold preference over sigma-1 receptors. These compounds may be useful in developing effective pharmacotherapies for cocaine toxicity.

Publication types

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

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Brain / metabolism
  • Cocaine / toxicity*
  • Cocaine-Related Disorders / drug therapy
  • In Vitro Techniques
  • Ligands
  • Mice
  • Oxazoles / chemical synthesis*
  • Oxazoles / chemistry
  • Oxazoles / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / metabolism*
  • Seizures / chemically induced
  • Seizures / drug therapy
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Anticonvulsants
  • Ligands
  • Oxazoles
  • Piperazines
  • Receptors, sigma
  • Thiazoles
  • sigma-1 receptor
  • sigma-2 receptor
  • Cocaine