Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2775-9. doi: 10.1016/j.bmcl.2012.02.082. Epub 2012 Mar 2.

Abstract

We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacology*
  • Analgesics, Opioid / chemical synthesis*
  • Analgesics, Opioid / chemistry
  • Analgesics, Opioid / pharmacology*
  • Bridged-Ring Compounds / chemistry*
  • Bridged-Ring Compounds / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Receptors, Opioid, kappa / agonists*

Substances

  • Amides
  • Analgesics, Opioid
  • Bridged-Ring Compounds
  • Receptors, Opioid, kappa