Synthesis and biological activity of opioid analgesics

Abstract

A variety of buprenorphine analogs have been synthesized. In the studies of analgesic and addictive effects in mice and $[^{35}S]GTP\gammaS$ binding assay in human brain tissue, the new compound 16 has been identified as a selective κ partial agonist which gives antinociceptive effects, but is not self-administered. It is reported that the activation of κ receptors leads to the suppression of unpleasant μ- and δ-mediated side effects such as the rewarding effect. The fact that this compound has a profile (κ partial agonist) may lead to lower degrees of dysphoria than full κ agonists. The compound may be valuable for the development of long-lasting analgesic, as a requirement for protracted use in neuropathic pain and drug abuse medication. In addition, a new method for the efficient radical deoxygenation of alcohols is described for preparing bulk chemicals avoiding scale-up problems. Treatment of various thiocarbonyl derivatives with $(Bu_4N)_2S_2O_8$ and $HCO_2Na$ in DMF afforded the corresponding deoxygenated products in excellent yields. The deoxygenation appears to be initiated by the transfer of a single electron to thiocarbonyl derivatives from $CO_2^{\bullet -}$ rather than from $SO_4^{\bullet -}$. This type of reduction is especially important in many areas of natural product chemistry such as sugars, glycosides, and nucleosides since a selective deoxygenation of the hindered hydroxy-groups is often required in order to enhance their biological activities. Of particular note, in the case of 27c (phenyl thionocarbonate) the $(Bu_4N)_2S_2O_8/DCO_2Na$ deoxygenation system in DMSO can provide the deuterated furanose derivatives at C3 position.