Diels-Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-04, Vol.27 (9), p.2863
• Main Authors: Marton, János, Fekete, Anikó, Cumming, Paul, Hosztafi, Sándor, Mikecz, Pál, Henriksen, Gjermund
• Format: Article
• Language: English
• Subjects: Adducts; Affinity; Agonists; Analgesics; Analgesics - pharmacology; Analgesics, Opioid - pharmacology; Brain research; Buprenorphine; Cycloaddition; Diels-Alder reactions; Diels–Alder reaction; Drug abuse; Drug addiction; Etorphine; Grignard addition; Investigations; Ligands; Molecular structure; morphinan-6,8-dienes; Morphinans - pharmacology; Morphine; Morphine - pharmacology; morphine alkaloids; Naloxone; Naloxone - pharmacology; Narcotics; Nervous system; O-demethylation; Opioid receptors; Pain; Physiology; Receptors, Opioid; Receptors, Opioid, mu - agonists; Review; Tomography
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27092863

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20 -etorphine and 20 -dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels-Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.