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Structure‐Activity Relationships of Oxygenated Morphinans. I. 4‐Mono‐ and 3,4‐dimethoxy‐ N ‐methylmorphinans and ‐ N ‐methyl‐morphinan‐6‐ones with unusually high antinociceptive potency. Preliminary communication

1981; Wiley; Volume: 64; Issue: 5 Linguagem: Inglês

10.1002/hlca.19810640506

1522-2675

Arthur E. Jacobson, Fu‐Lian Hsu, Maria D. Rozwadowska, Helmut Schmidhammer, Louise Atwell, Arnold Brossi, Fedor Medzihradsky,

Pain Mechanisms and Treatments

Abstract The antinociceptive potency and receptor affinity of several optically active aromatic mono‐ and di‐oxygenated N ‐methylmorphinans and N ‐methylmorphinan‐6‐ones, prepared from natural morphine, were determined. Thus, in order of antinociceptive potency, 4‐methoxy‐ N ‐methylmorphinan‐6‐one ≈ 3,4‐dimethoxy‐ N ‐methylmorphinan‐6‐one ≈ 3,4‐dimethoxy‐ N ‐methylmorphinan > 4‐methoxy‐ N ‐methylmorphinan ≈ 4‐acetoxy‐ N ‐methylmorphinan‐6‐one > 4‐acetoxy‐ N ‐methylmorphinan ≈ 4‐hydroxy‐ N ‐methylmorphinan‐6‐one ≈ 4‐hydroxy‐ N ‐methylmorphinan. The 4‐hydroxy compounds were slightly less potent than morphine, and the 4‐methoxy and 3,4‐dimethoxy compounds were found to have three times the potency of morphine. 4‐Methoxy‐ N ‐methylmorphinan‐6‐one showed an opiate receptor affinity one‐third that of morphine; this is a remarkably high affinity for a non‐phenolic compound.