The NIH Opiate Total Synthesis has been refined and its versatility extended in synthetic studies currently directed at unnatural opiate enantiomers. This route in its present form now renders either enantiomer of codeine, morphine and thebaine available in nearly 30% overall yield from m-methoxyphenethylamine with only 6-8 isolated intermediates. These results now offer, for the first time, a commercial source of medical opiates independent of the opium poppy. N-Cycloalkylmethylnorthebaine derivatives are also available in about 20% yield from the same starting material. That the medically valuable drugs nalbuphine and naltrexone can be directly synthesized in good overall yield from these northebaine derivatives has been demonstrated. Bivalent agonist and antagonist opiate ligands containing either 2 natural or 1 natural and one unnatural opiate moieties were synthesized. The steroselectivity of potency enhancement observed further supported the hypothesis that opiate receptors are the vicinal recognition sites involved in the bridging of bivalent opiate ligands. A number of unnatural enantiomers of opium-derived agonists and antagonists have been synthesized to study the mechanism of cough. The natural and unnatural enantiomers of codeine have been tritiated to high specific activity for further characterization of the binding sites which control this reflex.
