page_title: Peripherally acting μ-opioid receptor antagonist
section_title: Structure
hierarchical_section_title: Peripherally acting μ-opioid receptor antagonist / Structure–activity relationship / Structure
caption_attribution_description: English: The similarity in structural characteristics of MOR-antagonists
context_page_description: Peripherally acting μ-opioid receptor antagonists are a class of chemical compounds that are used to reverse adverse effects caused by opioids interacting with receptors outside the central nervous system, mainly those located in the gastrointestinal tract. PAMORAs are designed to specifically inhibit certain opioid receptors in the gastrointestinal tract and with limited ability to cross the blood-brain barrier. Therefore, PAMORAs do not affect the analgesic effects of opioids within the central nervous system.
context_section_description: Methylnaltrexone bromide, naloxegol, and naldemedine all have similar structures, which is not far away from the chemical structure of morphine and other MOR-agonists. All contain a rigid pentacyclic structure that involves benzene ring (A), tetrahydrofuran ring (B), two cyclohexane rings (C and D) and a piperidine ring (E). The most important functional groups for the biological action of opioids are the hydroxyl group on the phenol, N-methyl group, ether bridge between C4 and C5, the double bond between carbon number C7 and C8 and the hydroxyl groups at C3 and C6. The phenolic ring and its 3-hydroxyl group is vital for the analgesic effects as the removal of the OH group decrease the analgesic activity 10-fold. There is another principle for the hydroxyl group on C6 as the removal enhances its activity. The increased activity is mainly because of the increased lipophilicity and the increased ability to cross the blood-brain barrier. Naldemedine has the hydroxyl group while methylnaltrexone bromide has a ketone group and naloxegol has an ester. The double bond between C7 and C8 is not required for the analgesic effect and reduction of the double bond will increase the activity. None of the antagonists has a double bond in their structure. The N-substituent on the skeleton is thought to determine the pharmacological behavior and its interaction with MOR. It is also thought to play a key role in distinguishing antagonists from agonists. Allyl group, a methylcyclopropyl group or a methylcyclobutyl as N-substituent groups are thought to lead antagonist activity.
caption: The similarity in structural characteristics of MOR-antagonistsA = Benzene ring, B = Tetrahydrofuran, C, D = Cyclohexane rings, E = Piperidine ring
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