Structural Classes of Antagonist

Structure-activity relationships of the many antagonists and dualists developed since the revival of interest in nalorphine are dominated by (1) the nature of the supporting skeleton, (2) the influence of the N-substituent on the pharmacological profile, and (3) the concept of a pure antagonist.  

Apart from a few notable exceptions (see later), all known narcotic antagonists are based on the morphine, morphinan, or benzomorphan polycyclic systems, that is, on three closely related groups of opioid ligands that share many structure-activity relationships (see Chapters 2, 3, and 4). Details of antagonist representatives of each group will now be given, chiefly confined to N- allyl and N-cyclopropylmethy 1 (CPM) derivatives, with minimal chemical details. 

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The potent (IC50 = 8.9 nM, rat uterus 26 nM, human uterus), orally available (bioavailability 21% in three species) oxytocin antagonist L-368,899 is currently undergoing clinical evaluation. The authors are continuing their efforts to increase the understanding of the relationship between the nonpeptide and peptidic oxytocin antagonists. The aim of this work is to develop a pharmacophore model that will assist in the discovery of new structural classes of antagonists. 

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