Structure-Activity Relationships of a Novel Series of Extremely Po - Tent Analgesics With an Unusually High Safety Margin

Bever, Willem F. M. Van

doi:10.1016/b978-0-08-021308-8.50108-3

Cited by 12 publications

(15 citation statements)

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“…carfentanil and remifentanil. 2,25,29 Comparison of the position and conformation of fentanyl in different binding modes. The WE simulations demonstrated that the two fentanyl binding modes are readily accessible from one another in the presence of HID297 (Fig.…”

Section: Further Comparison Between the Configurations From The We-himentioning

confidence: 99%

“…1 The surge in fentanyl is attributed to high potency (50-400 times more potent than the naturally occurring morphine), fast onset, straightforward synthesis, and low cost production. [2][3][4][5] Additionally, the fentanyl core is readily modified creating a vast chemical space of fentanyl analogs with abuse potential. 6 Fentanyl and morphine opioids produce strong analgesic responses through binding and subsequent activation of a class A G protein-coupled receptor (GPCR) µ-opioid receptor (mOR).…”

Section: Introductionmentioning

confidence: 99%

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How mu-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

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The opioid crisis has escalated during the COVID-19 pandemic. More than half of the overdose-related deaths are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, crystal structures of mOR complexed with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like synthetic opioids remains lacking. Exploiting the X-ray structure of mOR bound to a morphinan ligand and several state-of-the-art simulation techniques, including weighted ensemble and continuous constant pH molecular dynamics, we elucidated the detailed binding mechanism of fentanyl with mOR. Surprisingly, in addition to the orthosteric site common to morphinan opiates, fentanyl can move deeper and bind mOR through hydrogen bonding with a conserved histidine H297, which has been shown to modulate mOR's ligand affinity and pH dependence in mutagenesis experiments, but its precise role remains unclear. Intriguingly, the secondary binding mode is only accessible when H297 adopts a neutral HID tautomer. Alternative binding modes and involvement of tautomer states may represent general mechanisms in G protein-coupled receptor (GPCR)-ligand recognition. Our work provides a starting point for understanding mOR activation by fentanyl analogs that are emerging at a rapid pace and assisting the design of safer analgesics to combat the opioid crisis. Current protein simulation studies employ standard protonation and tautomer states; our work demonstrates the need to move beyond the practice to advance our understanding of protein-ligand recognition.

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Section: Further Comparison Between the Configurations From The We-himentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

How mu-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

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show abstract

“…carfentanil and remifentanil. 3,34,36,39 Comparison of the position and conformation of fentanyl in different binding modes. The WE simulations demonstrated that the two fentanyl binding modes are readily accessible from one another in the presence of HID297 (Fig.…”

Section: Further Comparison Between the Configurations From The We-himentioning

confidence: 99%

“…2 The surge in fentanyl is attributed to high potency (50-400 times more potent than the naturally occurring morphine), fast onset, straightforward synthesis, and low cost production. [3][4][5][6] Additionally, the fentanyl core is readily modified creating a vast chemical space of fentanyl analogs with abuse potential. 7 Fentanyl and morphine opioids produce strong analgesic responses through binding and subsequent activation of a class A G protein-coupled receptor (GPCR) µ-opioid receptor (mOR).…”

Section: Introductionmentioning

confidence: 99%

Howµ-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

View full text Add to dashboard Cite

The opioid crisis has escalated during the COVID-19 pandemic. More than half of the overdose-related deaths are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, crystal structures of mOR complexed with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like synthetic opioids remains lacking. Exploiting the X-ray structure of mOR bound to a morphinan ligand and several state-of-the-art simulation techniques, including weighted ensemble and continuous constant pH molecular dynamics, we elucidated the detailed binding mechanism of fentanyl with mOR. Surprisingly, in addition to the orthosteric site common to morphinan opiates, fentanyl can move deeper and bind mOR through hydrogen bonding with a conserved histidine H297, which has been shown to modulate mOR’s ligand affinity and pH dependence in mutagenesis experiments, but its precise role remains unclear. Intriguingly, the secondary binding mode is only accessible when H297 adopts a neutral HID tautomer. Alternative binding modes and involvement of tautomer states may represent general mechanisms in G protein-coupled receptor (GPCR)-ligand recognition. Our work provides a starting point for understanding mOR activation by fentanyl analogs that are emerging at a rapid pace and assisting the design of safer analgesics to combat the opioid crisis. Current protein simulation studies employ standard protonation and tautomer states; our work demonstrates the need to move beyond the practice to advance our understanding of proteinligand recognition.

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“…It has already been observed that the more hydrophilic or ionized substituents lead to analgesics with less lipid solubility (lower partition coefficients), little or no accumulation in fat tissues, and rapid excretion [56]. It appears that the chemical nature of the substituent in the position 4 of the piperidine ring of fentanyl, also has little influence on potency, since groups as diverse as carbomethoxy, methoxymethyl, hydroxymethyl, methylketone, methyl and aryl, all cause significant rise (2-30 times) in potency compared to fentanyl [29,41,57]. For example, the shorter duration of action of 3-carbomethoxy fentanyl could be due to susceptibility of the carbomethoxy group to rapid hydrolysis by non-specific esterases, as is the case with the ultra-short-acting fentanyl analog remifentanil [11].…”

Section: Trans-3-butyl Fentanyl Trans-3-benzyl Fentanyl Trans-3-phenementioning

confidence: 99%

Fentanyl Analogs: Structure-Activity-Relationship Study

Vučković¹,

Prostran

Ivanović

et al. 2009

CMC

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Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

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Structure-Activity Relationships of a Novel Series of Extremely Po - Tent Analgesics With an Unusually High Safety Margin

Cited by 12 publications

References 0 publications

How mu-Opioid Receptor Recognizes Fentanyl

How mu-Opioid Receptor Recognizes Fentanyl

Howµ-Opioid Receptor Recognizes Fentanyl

Fentanyl Analogs: Structure-Activity-Relationship Study

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