Synthetic route optimization and optical resolutions of hydrocodone congeners for opioid dependence studies

Thursday, November 07, 2013 — Poster Session II
12:00 p.m. – 2:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIDA	CHEMCELL-23

Authors

B.R. Selfridge
J.R. Deschamps
A.E. Jacobson
K.C. Rice

Abstract

A longstanding method of treatment for both short term and chronic pain management has been the use of opioid analgesics such as morphine and it’s derivatives both natural and synthetic. These opioids modes of action are known to exist via interactions with the three main opioid receptors (μ, δ, κ). It has long been a goal of medicinal chemists to create compounds that simultaneously induce analgesia without emergence of undesired side effects such as tolerance and dependence. A racemic hydrocodone congener lacking a bridging benzylic carbon was initially synthesized by Weller et. al. in the early 1980’s. A Dupont Merck group led by Cheng resynthesized this racemic mixture along with the N-cyclopropyl methyl derivative and evaluated them for opioid receptor binding along with their analgesic properties in mice. These compounds showed low nM binding to both the μ and δ opioid receptors, thus inducing analgesia. We have optimized the route to these compounds by removing chromatographic separations and drastically improving a few low yielding transformations. In addition, we have optically resolved the mixtures of enantiomers, so the opioid binding assays can be performed on each enantiomer, thus revealing the active components of the racemic mixtures.