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.
