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Synthesis and biological evaluation of 2-alkyl-2-methoxymethyl-salvinorin ethers as selective κ-opioid receptor
David Y W Lee1, Gang Deng1, Zhongze Ma1
1Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
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.
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