Peripherally acting μ-opioid receptor antagonist

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Peripherally acting

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.[1]

Discovery and development

Opioid drugs are known to cause

peristaltic waves leading to delayed absorption of medications and more water absorption from the feces. That can result in hard and dry stool and constipation for some patients.[2]

OIC is one of the most common

adverse effects caused by opioids, so the discovery of PAMORAs can prevent the effects that often compromise pain management.[3]

blood brain barrier, without affecting the analgesic effects of the opioids. After Goldberg died, his colleagues at the university continued to develop the compound. It was approved by the FDA in April 2008, originally for OIC in adult patients with advanced illness and later in adult patients with chronic noncancer pain.[5]

In the late 1970s, Dennis M. Zimmerman and his co-workers from

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.[7][8][9][10]

Mechanism of action

PAMORAs act by inhibiting the binding of opioids

gut motility, gut secretion and sphincter function.[12]

PAMORAs effect on gut motility is that it can increase the resting tone in the circular muscle layer. The antagonist enhances the effect on tonic inhibition of the

abdominal cramp.[13]

PAMORAs effect on gut secretion will help reverse the decreased

peptides by increasing the sympathetic nervous system through the μ-receptors in the ENS, which can lead to drier and harder stool. PAMORAs work against it so the stool becomes softer and less dry.[13]

PAMORAs effect on the function of the

hemorrhoids and incomplete emptying.[16]

Structure–activity relationship

Even though μ-opioid receptor (MOR) targeting drugs have been used for a long time, not much is known about the

allyl- or cyclopropyl methyl at the morphinan nitrogen, while agonists generally contain a methyl group. On the other hand, agonist activity is also shown in ligands with larger groups at the morphinan nitrogen, and therefore this hypothesis is challenged.[17]

Structure

The similarity in structural characteristics of MOR-antagonistsA = Benzene ring, B = Tetrahydrofuran, C, D = Cyclohexane rings, E = Piperidine ring

Methylnaltrexone bromide, naloxegol, and naldemedine all have similar structures, which is not far away from the chemical structure of

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.[19][20][21]

Binding site

Agonists and antagonists form certain

amino acids that construct the MOR. The majority of antagonists, as well as agonists, are predicted to form charged interaction with Asp147 and a hydrogen bond with Tyr148. However, majority of antagonists also form additional polar interactions with other amino acid residues such as Lys233, Gln124, Gln229, Asn150, Trp318 and Tyr128. Only a small minority of agonists form the same additional polar interactions. Both agonists and antagonists are known to form hydrogen bonds with His297.[22]

It can be concluded that interactions with the amino acid residues, Asp147 and Tyr148 are essential for the ligand to bind to the receptor and the molecules that form additional polar interactions with other residues are more often antagonists than agonists.[17]

The N-substituent group can form

hydrophobic bonds with Tyr326 and Trp293 and the aromatic and cyclohexane rings can form similar bonds to Met151. The backside of the ligand can also form a hydrophobic bond, but with Val300 and Ile296.[22]

Methylnaltrexone bromide

Methylnaltrexone bromide is the

affinity for MOR than for κ-opioid receptor (KOR) and δ-opioid receptor (DOR).[23] Naltrexone forms interaction with Asp147 and Tyr148 along with a hydrogen bond with Lys233.[24]

Different development stages of methylnaltrexone bromide. 1. Noroxymorphone 2. Naltrexone 3. Methylnaltrexone 4. Methylnaltrexone bromide

Alvimopan

The development of alvimopan from 4-(3-hydroxyphenyl)-3,4-dimethylpiperidine

Peripherally selective trans-3,4-dimethyl-4-(3-hydroxylphenyl)piperidine opioid antagonists were developed for the treatment of

zwitterionic structure and the high polarity prevents Alvimopan from crossing the blood–brain barrier, potency at binding peripheral MORs is thereby 200 times that of central MORs.[25]

Naloxegol

Naloxegol is a

efflux transporter that transports the compound out of the CNS.[27]

Naldemedine

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. Like naloxegol, naldemedine is a substrate of the P-glycoprotein efflux transporter. These properties result in less penetration into the CNS and decrease possible inference with the effects of opioid agonists.[28]
Naldemedine is a dual antagonist for MOR and DOR. Activation of the DOR has been known to cause nausea and/or vomiting, so a dual antagonist can decrease both OIC and nausea/vomiting.[29]

Pharmacokinetics

The

binding affinity are present in the table below.[26][23]

Table 1: Pharmacokinetic parameters of peripherally acting μ-opioid receptor antagonists[30][5][31][32][33][34]
Chemical name Chemical structure Molecular weight (g/mol) Bioavailability (%) Plasma protein binding (%) t1/2 (h) tmax Ki μ (nM) Ki κ (nM) Ki δ (nM)
Methylnaltrexone bromide
436,3 Low 11-15 8 30 min 5.50 32.1 3453.8
Alvimopan

424,53 6 80-90 10-17 2 h 0.77 40 4.4
Naloxegol

651,798 NA 4,2 6-11 2 h 7.42 8.65 203.0
Naldemedine

570,6 29 93-94 11 45 min 0.34 0.94 0.43

Methylnaltrexone bromide has poor oral bioavailability, and for that reason, every other day it is administered

subcutaneously. About half of the dose is excreted in the urine and somewhat less in feces with 85% eliminated unchanged.[24]

Alvimopan has considerable low bioavailability (6%) due to its high

intestinal flora resulting in hydrolysis of alvimopan to the active amide metabolite (ADL 08-0011). However, the metabolite is considered clinically irrelevant due to its low binding affinity.[25]

When naloxegol is given with a fatty meal,

renal excretion.[30]

Naldemedine metabolites mainly via

parent compound.[35]

PAMORAs in development

Structure of axelopran

clinical trials in more than 400 patients with OIC. Axelopran has a different chemical structure from other PAMORAs but with a similar mechanism of action. It acts as an antagonist for MOR, KOR and DOR, but with higher affinity for MOR and KOR than for DOR. Like other PAMORAs, the main goal is the treatment of OIC.[36]
Axelopran is also being investigated in fixed-dose combination (FDC) with oxycodone. It is done by using spray coating technology to create an FDC of axelopran and controlled-release oxycodone.[37]

There is a demand for optimization of the receptor selectivity and affinity accompanied by an exploration of candidate compounds regarding their route of administration. These are the main objectives and future strategies for drug discovery and the development of PAMORAs. Predominantly, the MORs exhibit functionally selective agonism. Therefore, future possible candidate compounds that target OIC are PAMORAs with optimized selectivity and affinity.[27]

References

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  30. ^ a b Turan, Alparslan; Saasouh, Wael; Hovsepyan, Karen; You, Jing. "Ancillary Effects of Oral Naloxegol (Movantik)" (PDF). Clinicaltrials.gov.
  31. ^ "Alvimopan (ADL 8-2698) | Opioid Receptor Antagonist | MedChemExpress". MedchemExpress.com.
  32. ^ "Methylnaltrexone bromide". pubchem.ncbi.nlm.nih.gov.
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  37. ^ "Theravance Biopharma: Programs | Gastrointestinal Motility Dysfunction". SITE.


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