We first prepared and characterized unnatural (+)-naloxone in 1978 as an opioid receptor inert research tool useful for detecting opioid receptor mediated effects when used in conjunction with (-)-naloxone, a high affinity clinical useful narcotic antagonist. We know now that (+)-naloxone and (+)-naltrexone, long thought to be inert compounds, are functional antagonists of TLR-4 receptors and that selective acute functional antagonism of TLR-4 by (+)-naloxone results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Earlier we introduced the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation was demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. In order to provide more conformationally mobile analogs of (+)-naltrexone for pharmacological study as functional antagonists TLR-4, we developed a nonchromatographic total synthesis of chiral 10-nornaltrexone via 10-nordihydrocodeinone. Optical resolution of 10-nordihydrocodeinone provided the enantiomers. Single crystal x-ray analysis of the salt of (+)-2 with R-mandelic acid showed that the absolute configuration of (+)-2 was analogous with that of unnatural (+)-morphine. Treatment of (+)-2 with trimethylorthoformate and 5-sulfosalacyclic acid gave (+)-10-nor-8,14-dihydrothebaine. Reaction of the latter with N-bromoacetamide/methanesulfonic acid in methanol gave 10-nor-7-bromodihydrocodeinone dimethylketal. This was converted in 2 steps to (+)-10-northebaine that afforded (+)-10-nornaltrexone using methods similar to the conversion of (-)-thebaine to (-)-naltrexone. Similarly (-)-10-nordihydrocodeinone was converted to (-)-10-nornaltrexone. Opioid receptor binding studies showed that (-)-10-nornaltrexone selectively bound to the mu-receptor with about 4 times the affinity of (-)-morphine and to the kappa receptor with about 40 times less affinity than (-)-naltrindole.
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