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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.
Effect of laparoscopic sleeve gastrectomy on drug pharmacokinetics
Published in Expert Review of Clinical Pharmacology, 2021
Kaifeng Chen, Yaqi Lin, Ping Luo, Nan Yang, Guoping Yang, Liyong Zhu, Qi Pei
Dextrorphan is the O-demethylated metabolite of dextromethorphan, which can be further N-demethylated to form 3-hydroxymorphinan (morphinan-3-ol) by CYP3A4 [32]. The effect of body mass index and bariatric surgery (LSG and RYGB) on CYP3A4 activity was investigated both prior to surgery and at 1 month and 6 months after surgery [17]. CYP3A4 activity was markedly lower in patients with extreme obesity than in normal-weight controls. This could be explained by the fact that the dextrorphan/3-hydroxymorphinan ratio (CYP3A4-mediated substrate/product ratio) had a positive correlation with BMI. Interestingly, bariatric surgery normalized CYP3A4 activity. Although such effects were observed in both surgical types, they occurred earlier in LSG (with statistical significance achieved at 4 weeks post-operation and maintained at 6 months) as opposed to RYGB (for which statistical significance was noted at 6 months after surgery).
Emerging PEGylated non-biologic drugs
Published in Expert Opinion on Emerging Drugs, 2019
Eun Ji Park, Jiyoung Choi, Kang Choon Lee, Dong Hee Na
NKTR-181 [(5a,6a)-4,5-epoxy-6-(3,6,9,12,15,18-hexaoxanonadec-1-yloxy)-3-methoxy-17-methylmorphinan-14-ol] is an orally available μ-opioid agonist developed by Nektar Therapeutics and now is in clinical phase 3 development (ClinicalTrials.gov identifier: NCT02367820). This new chemical entity was designed to provide potent pain relief without the high levels of euphoria that can lead to abuse and addiction with standard opioids [75]. As a major cause of drug abuse of opioid analgesics is known to be rapid entry into the central nervous system, NKTR-181 employed short-chain PEG (<300 kDa) added to a morphine-like (morphinan) pharmacophore via ether linkage (Figure 2(b)), in which the PEG chain is expected to slow down brain uptake rate while retaining activity as a selective μ-opioid agonist. In rats, NKTR-181 had a 17-fold to 70-fold lower rate of brain entry compared with hydrocodone and oxycodone, respectively, although the maximum analgesic efficacy achieved was equivalent to oxycodone treatment [75].
Current strategies toward safer mu opioid receptor drugs for pain management
Published in Expert Opinion on Therapeutic Targets, 2019
Aliza T. Ehrlich, Brigitte L. Kieffer, Emmanuel Darcq
The concept of peripherally limited ligands arose from the desire to limit addictive central effects of opioids such as reward [53–56]. Peripherally limited compounds are generally designed to be hydrophilic to lower their ability to cross the blood brain barrier. Loperamide (Imodium) was the first commercial peripherally limited MOR agonist. Loperamide was also shown to reduce heat and mechanical hyperalgesia in nerve-injured rats [57] yet, in human it is not used as an analgesic. Since then, new designs have been used to generate peripherally limited MOR agonists including arylacetamide triazaspiro morphinan based (DiPOA), and peptidic compounds (DALDA) [53]. However, these new modifications have a disadvantage of reducing the ligand binding affinity at MORs and some of the compounds can still cross the blood brain barrier at high doses [53]. Another strategy has been to use morphine covalently attached to a hyperbranched polyglycerol (PG-M) by a cleavable linker to relegate morphine to peripheral release in selective inflamed tissue without crossing the blood-brain barrier [58]. This strategy offers safer opioid analgesics by peripherally restricting and surpassing central and intestinal side effects, however the efficacy of this approach still needs to be determined in humans.