Synthesis, x-ray crystallographic determination, and opioid activity of erythro-5-methylmethadone enantiomers. Evidence which suggests that .mu. and .delta. opioid receptors possess different stereochemical requirements

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Abstract
Enantiomers of erythro-5-methylmethadone (3) were synthesized from optical antipodes of erythro-3-(dimethyl-amino)-2-butanol. X-ray crystallographic analysis of (-)-3 perchlorate revealed that it possesses the 5S,6S absolute configuration. (-)-3 is substantially more potent than its enantiomer (+)-3 as an opioid agonist in vivo and in vitro. In vitro tests (guinea pig ileal longitudinal muscle and mouse vas deferens preparations) suggest that (-)-3 mediates its effect chiefly through .mu. opioid receptors. (+)-3 and the more potent enantiomers of methadone, (-)-1, and isomethadone, (-)-2, have less .mu.-receptor selectivity and interact with a greater fraction of .delta. receptors than does (-)-3. The fact that the solid-state conformation of (-)-3 differs from that of (-)-1 and (-)-2, which show great similarity in conformational features, suggests that .mu. and .delta. receptors have different conformational requirements. The possibility of different modes of interaction with a single opioid receptor population also is discussed.

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