Endo-ethenotetrahydrothebaines

Conformational studies of diastereoisomeric alcohols of the 6,14-endo-ethenotetrahydrothebaine series, using a PCILO semi-empirical quantum-mechanical method, have been made in relation to the different agonist/ antagonist properties of the isomers.170 [N-Methyl-11 C]- and [N-methyl-14C]-morphine have been prepared.171,172... 

Ozonolysis<359) of 6,14-endo-ethenotetrahydrothebaines has afforded aromatic ring cleaved products. Tertiary alcohols (214, R = Me, R1 = alkyl R2 = Me, n-Pr or CBM), for example, gave the lactonic esters 220, which had analgesic potencies similar to that of morphine. This somewhat surprising result suggested that the aromatic pharmacophore in opioids was not an essential feature for a compound to elicit opioid-like responses. The authors(359) indicated that this could be the case if pharmacophores elsewhere in the molecule compensated for the loss of aromatic binding. 

Diels-Alder adducts of thebaine may exhibit exceptionally high levels of opioid activity. The crystal structure of 7a-(l-(i )-hydroxy-l-methylbutyl)-6,14-endo-ethenotetrahydrothebaine hydrobromide (Etorphine 221) was determined 00 and the C-ring cage structure was found to be severely distorted relative to the idealized Dreiding model. 

Other compounds of potential pharmacological interest have been prepared in the 6,14-endo-ethenotetrahydrothebaine series by nuclear substitution/ modification of the C-7 substituent/3,6-0-demethylation/ removal of the C-3 oxygen function/ and by ozonolysis/ The last of these reactions involves fission of the aromatic nucleus, and, surprisingly, affords compounds that still show potent analgesic activity. 

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