Synthesis and biological evaluation of 2-alkyl-2-methoxymethyl-salvinorin ethers as selective κ-opioid receptor agonists.
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.
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
David Y W
DY
Lee
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Gang
G
Deng
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Zhongze
Z
Ma
Department of Pharmacology and Center for Substance Abuse Research, School of Medicine, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
Wei
W
Xu
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Lu
L
Yang
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Jing
J
Liu
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Ronghua
R
Dai
Department of Pharmacology and Center for Substance Abuse Research, School of Medicine, Temple University, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
Lee-Yuan
LY
Liu-Chen
D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008968:Molecular Conformation; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
D004224:Diterpenes; D017473:Receptors, Opioid, kappa
Affinity; Agonist; Receptor; κ-opioid