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.
David Y W Lee  1 ,  Gang Deng  1 ,  Zhongze Ma  1 ,  Wei Xu  2 ,  Lu Yang  1 ,  Jing Liu  1 ,  Ronghua Dai  1 ,  Lee-Yuan Liu-Chen  2
Affiliations
  • 1. Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
  • 2. Department of Pharmacology and Center for Substance Abuse Research, School of Medicine, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
PMID: 26330078 DOI: 10.1016/j.bmcl.2015.06.092
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.