Peripherally acting μ-opioid receptor antagonist
Peripherally acting μ-opioid receptor antagonists (PAMORAs) are a class of chemical compounds that are used to reverse adverse effects caused by opioids interacting with receptors outside the central nervous system (CNS), 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.
Having witnessed the suffering of a dying friend with OIC, Goldberg tested various derivatives of naltrexone, a drug known to block the effects of opioids.
His objective was to find a drug that could not pass the blood brain barrier, without affecting the analgesic effects of the opioids.
[5] Alvimopan was approved later in 2008 for in-hospital use to increase the gastrointestinal function following a partial large or small bowel resection with primary anastomosis.
Naloxegol was approved in September 2014 and naldemedine in March 2017, both for the treatment of OIC in adult patients with chronic cancer.
The objective of PAMORAs treatment is to restore the enteric nervous system function (ENS).
The MORs in the gastrointestinal tract are the main receptors that PAMORAs are intended to block and prevent the binding of opioid agonists.
[11] PAMORAs are used in the treatment of opioid-induced bowel dysfunction (OIBD), a potential adverse effect caused by chronic opioid use.
[12] PAMORAs effect on gut motility is that it can increase the resting tone in the circular muscle layer.
[13] PAMORAs effect on gut secretion will help reverse the decreased cAMP formation that opioid agonists induce.
Opioids agonists can also reduce the secretion of peptides by increasing the sympathetic nervous system through the μ-receptors in the ENS, which can lead to drier and harder stool.
On the other hand, agonist activity is also shown in ligands with larger groups at the morphinan nitrogen, and therefore this hypothesis is challenged.
The majority of antagonists, as well as agonists, are predicted to form charged interaction with Asp147 and a hydrogen bond with Tyr148.
The methyl group and the quaternary salt formation increase the polarity and reduce the lipid solubility thereby restricts the blood–brain-barrier penetration.
[24] Peripherally selective trans-3,4-dimethyl-4-(3-hydroxylphenyl)piperidine opioid antagonists were developed for the treatment of gastrointestinal motility disorder by Zimmerman and his coworkers.
From that, they derived the 4-(3-hydroxyphenyl)-3,4-dimethylpiperidine scaffold with functional groups spanning various sizes, charge, and polarity to reach peripheral opioid receptor antagonism while decreasing CNS drug exposure.
The in vitro μ-Ki, in vivo AD50, and ED50 and peripheral index (ratio) was examined for several selective analogs, and from that, they found out that the trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, Alvimopan, gave the best results.
Naloxegol has a similar form as naloxone as a heteropentacyclic compound both of which have an allyl group attached to the amine of the piperidine ring.
[27] Naldemedine has a similar chemical structure as naltrexone but with an additional side chain that increases the molecular weight and polar surface area of the substance.
[35] There is a demand for optimization of the receptor selectivity and affinity accompanied by an exploration of candidate compounds regarding their route of administration.
