4.5- Epoxymorphinans antagonists

Antagonist actions in 4,5-epoxymorphinans are often substantially increased when oxygen is introduced into the molecule at C-14(264), and several explanations have been offered for this phenomenon. 265"268 In particular, the effect of a 14/3-OH function upon the JV-substituent and its directionality, 269 270 or upon molecular conformation, 271 153 has been given some consideration. The suggestion 272 that the 14-OH interacts both with the protonated tertiary nitrogen and with loW-energy conformers of the N-substituent at a common anionic site on the opioid receptor has been tested 273 by the... 

Various aspects of structure activity relationships in 4,5-epoxymorphinans have been reviewed,(201,46 U467) and specific consideration has been given to quantum chemical studies with particular reference to polar group variation,(468) stereoisomeric ligands as receptor probes, 469 partition and distribution coefficients, 470 471 and antagonists. 145 ... 

Work on the relationship between chemical structure and pharmacological activity of morphinans to 1966 has been reviewed by Hellerbach et al. s) and morphinans with antagonist properties were reviewed in 1973.(158) As is the case for 4,5-epoxymorphinans (Chapter 2) and benzomorphans (Chapter 4), molecular geometry is the major structure-biological activity influence, although the nature of the N-substituent imparts significant qualitative and quantitative variations in morphinan pharmacology. 

The influence of a 14-OH substituent in 4,5-epoxymorphinans is reflected in the morphinan series Antagonist activities in N-CPM, N-CBM, and N-allyl series are increased relative to corresponding 14-H analogs, and they exert relatively weak analgesic actions This applies, regardless of the 14-OH configuration (i e, morphinan or isomorphinan) The introduction of a 6-oxo function into such structures enhances agonist responses... 

To design a new agonist, we first attempted to remove the accessory site of nor-BNI and maintain the message and address sites. The message site of nor-BNI, a 4,5-epoxymorphinan skeleton with a cyclopropylmethyl substituent, was considered to be indispensable for opioid activity because it corresponded to the tyrosine of endogenous opioid peptides. Therefore, we postulated that the accessory site of nor-BNI was located in the address subsite of this antagonist. 

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