Synthesis and biological evaluation of 2-alkyl-2-methoxymethyl-salvinorin ethers as selective κ-opioid receptor agonists

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4689-92. doi: 10.1016/j.bmcl.2015.06.092. Epub 2015 Jul 3.

Abstract

The synthesis of a new series of C-2-alkyl-2-methoxymethyl-salvinorin ethers and their binding affinities at κ-, μ-, and δ-opioid receptors are presented. We have developed a synthesis that enables installation of alkyl-substituents at C-2 while maintaining the integrity of the C-2 methoxymethyl ether and retaining κ-opioid receptor binding activity. Among these new compounds, 2-methyl-2-methoxymethyl-salvinorin ether (9a) is a potent full agonist at the κ receptor and shows comparable potency in Ki and EC50 with salvinorin A and U50488H. These C2-alkylated analogs have been identified as full κ agonists.

Keywords: Affinity; Agonist; Receptor; κ-opioid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Conformation
  • Receptors, Opioid, kappa / agonists*
  • Structure-Activity Relationship

Substances

  • Diterpenes
  • Receptors, Opioid, kappa