Improving selectivity preserving affinity: new piperidine-4-carboxamide derivatives as effective sigma-1-ligands

Eur J Med Chem. 2015 Jan 27:90:797-808. doi: 10.1016/j.ejmech.2014.12.018. Epub 2014 Dec 12.

Abstract

We report the design, synthesis and binding evaluation against σ1 and σ2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on σ receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Very high σ1 affinity (Ki = 3.7 nM) and Kiσ2/Kiσ1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom.

Keywords: Piperidine-4-carboxamide derivatives; Radioligand binding assays; σ-Receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Receptors, sigma / antagonists & inhibitors*
  • Sigma-1 Receptor
  • Structure-Activity Relationship

Substances

  • Ligands
  • Piperidines
  • Receptors, sigma
  • piperidine-4-carboxamide