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Narcotic Analgesics And Antagonists
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Work with derivatives of the opium alkaloids was sporadic after 1939, due to the discovery of pethidine. Later, after the morphinans achieved considerable success, most medicinal chemists were occupied with removing as much of the morphine skeleton as possible in the hope of simultaneously removing the side effects of morphine. This work also met with success, and so the opium alkaloids were fairly neglected until Bentley and co-workers22,23 decided to go in a direction opposite to that of most medicinal chemists. They reasoned that the separation of the desired from the undesirable properties of morphine might more easily be achieved by the preparation of more rigid and complex structures, claiming these structures would be more selectively adsorbed at the receptor sites. They began by using the opium alkaloid thebaine (Formula 11). A Diels-Alder reaction with dienophiles across the double bond system in thebaine produced compounds with activity comparable to pethidine, at first. later, using different dienophiles with thebaine and then with the derived oripavine (Formula 12), they obtained compounds with about ten thousand times the activity of morphine in some animal tests.24 These are, by far, the most active analgesics known. The parent compound of the series, 6, 14-endoethenotetrahydrothebaine (Formula 13), a 6, 14-ethano bridged derivative of codeine, is 40 times as potent as morphine.
Catalog of Herbs
Published in James A. Duke, Handbook of Medicinal Herbs, 2018
Toxicity — Etorphine, or M99, one of the “Bentley Compounds” derived from thebaine, is much used to sedate large wild animals for scientific purposes.17 Toxic activities of some of the alkaloids are discussed by Duke.241 The dependence potential of thebaine is partially attributed to oripavine, one of the principal metabolites of thebaine. The analgesic potency of oripavine in mice is higher than that of thebaine and comparable to morphine.244 At doses of 4 mg/kg rats show preconvulsive disorders, hyperirritability, tremor, muscle rigidity, motor impairment, and transient muscle contraction. At 5 mg/kg the rats died immediately in a persistent tonic seizure. Thebaine has an LD30 of 20 mg/kg in mice. In chicken embryos, thebaine is reported to induce pseudohyperfeminization.245
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Outstanding findings have also described the participation of CYP2D6 and CYP3A4 in the biosynthesis of morphine in liver and brain (Grobe et al. 2009; Kramlinger et al. 2015). CYP2D6 catalyzes three reactions in the biosynthesis of morphine, it catalyzes the 3-O-demethylation of codeine to morphine, the 3-O-demethylation of thebaine to oripavine, and the phenol coupling of (R)-reticuline to salutaridine (Figure 3) (Dayer et al. 1988; Mikus et al. 1991; Grobe et al. 2009).