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

Molecules

János Marton¹  Anikó Fekete²  Pál Mikecz²  Paul Cumming³  Sándor Hosztafi⁴  Gjermund Henriksen⁵ 

[1] ABX Advanced Biochemical Compounds Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany;Department of Medical Imaging, Division of Nuclear Medicine and Translational Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary;Department of Nuclear Medicine, Bern University Hospital, Freiburgstraße 18, 3010 Bern, Switzerland;Institute of Pharmaceutical Chemistry, Semmelweis Medical University, Högyes Endre utca 9, H-1092 Budapest, Hungary;Norwegian Medical Cyclotron Centre Ltd., Sognsvannsveien 20, N-0372 Oslo, Norway;

关键词: morphine alkaloids;    opioid receptors;    morphinan-6,8-dienes;    Diels–Alder reaction;    Grignard addition;    O-demethylation;   

DOI  :  10.3390/molecules27092863

来源: DOAJ

【 摘 要 】

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 20R-etorphine and 20R-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.

【 授权许可】

Unknown