Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

Kumar, Vinod; Ridzwan, Irna Elina; Grivas, Konstantinos; Lewis, John W.; Clark, Mary Jo; Meurice, Claire; Jimenez‐Gomez, Corina; Pogozheva, Irina D.; Mosberg, Henry I.; Traynor, John R.; Husbands, Stephen M.

doi:10.1021/jm401964y

Cited by 19 publications

(32 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1b and analogues differ from 15 only in the location of this single methyl, yet in the 1b series, only the parent compound (R = Ph) and the 3′-chloro analogue ( 1c : R = 3-ClPh) had low efficacy at KOPr (19 and 26%, respectively), with other substituents (2′-, 3′-, and 4′-methyl, 3′- and 4′-F) all resulting in efficacy in the range 77–102% at this receptor. 15 …”

Section: Discussionmentioning

confidence: 99%

“…This bias toward the S-isomer ( 5a ) parallels our findings on Grignard addition to the aldehyde of the related C7β-H series 14 and is opposite to that observed on addition of Grignard reagent to the methyl ketone in the C7β-H series. 14 , 15 Treatment of 5a with LiAlH 4 to reduce the amide before 3-O-demethylation gave 10a . To obtain the desired diastereoisomer, 5a was oxidized to the phenyl ketone ( 6a ) before LiAlH 4 reduction of both the cyclopropylcarbonyl group and the ketone, the latter occurring stereoselectively, to give 7a .…”

Section: Synthesismentioning

confidence: 99%

“… 14 However, we recently reported on a series of aryl analogues of buprenorphine, some of which displayed substantially lower efficacy at the opioid receptors while retaining high affinity for opioid receptors and moderate (equivalent to buprenorphine) affinity for NOPr. 15 We now report on a series of orvinol analogues in which the C20-methyl group has been moved to the C7-β position, resulting in more robust KOPr antagonism, enhanced NOPr activity, and low-efficacy partial agonism, or antagonism, at MOPr. A number of the ligands can be considered as single compound alternatives to the buprenorphine/naltrexone combination, while others offer potential as analgesics with a reduced side-effect profile.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

et al. 2015

Self Cite

View full text Add to dashboard Cite

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Medicinal chemists have developed several series of NOP receptor-related ligands with different efficacies on NOP and MOP receptors for distinct therapeutic applications (Calo & Guerrini, 2013; Husbands, 2013; Journigan, Polgar, Khroyan, & Zaveri, 2014; Kumar et al, 2014; Schunk et al, 2014; Toll, 2013; Zaveri, Jiang, Olsen, Polgar, & Toll, 2013). Table 1 highlights several mixed NOP/MOP receptor agonists, [Dmt 1 ]N/OFQ(1–13)-NH 2 (Molinari et al, 2013), SR14150 (Spagnolo et al, 2008), SR16435 (Khroyan, Polgar, Jiang, Zaveri, & Toll, 2009), SR16835 (Toll, Khroyan, Polgar, Jiang, Olsen, & Zaveri, 2009), and BU08028 (Khroyan, Polgar, Cami-Kobeci, Husbands, Zaveri, & Toll, 2011a), in terms of their antinociceptive and antihypersensitive actions.…”

Section: Therapeutic Potential Of Nop Receptor-related Agonists Asmentioning

confidence: 99%

Central N/OFQ-NOP Receptor System in Pain Modulation

Kiguchi

Ding

2016

Advances in Pharmacology

View full text Add to dashboard Cite

It has been two decades since the peptide, nociceptin/orphanin FQ (N/OFQ), and its cognate (NOP) receptor were discovered. Although NOP receptor activation causes a similar pattern of intracellular actions as mu opioid (MOP) receptors, NOP receptor-mediated pain modulation in rodents are more complicated than MOP receptor activation. In this review, we highlight the functional evidence of spinal, supraspinal, and systemic actions of NOP receptor agonists for regulating pain. In rodents, effects of the N/OFQ-NOP receptor system in spinal and supraspinal sites for modulating pain are bidirectional depending on the doses, assays, and pain modalities. The net effect of systemically administered NOP receptor agonists may depend on relative contribution of spinal and supraspinal actions of the N/OFQ-NOP receptor signaling in rodents under different pain states. In stark contrast, NOP receptor agonists produce only antinociception and antihypersensitivity in spinal and supraspinal regions of nonhuman primates regardless of doses and assays. More importantly, NOP receptor agonists and a few bifunctional NOP/MOP receptor agonists do not exhibit reinforcing effects (abuse liability), respiratory depression, itch pruritus, nor do they delay the gastrointestinal transit function (constipation) in nonhuman primates. Depending upon their intrinsic efficacies for activating NOP and MOP receptors, bifunctional NOP/MOP receptor agonists warrant additional investigation in primates regarding their side effect profiles. Nevertheless, NOP receptor-related agonists display a much wider therapeutic window as compared to that of MOP receptor agonists in primates. Both selective NOP receptor agonists and bifunctional NOP/MOP receptor agonists hold a great potential as effective and safe analgesics without typical opioid-associated side effects in humans.

show abstract

“…Buprenorphine is thought to have its therapeutic effect via the mu-and kappa-opioid receptors; However, buprenorphine also acts as a full agonist at the nociceptin opioid peptide (NOP) receptor (26). Therefore, expression of these opioid receptors was determined in hCS and hSS using RNA sequencing.…”

Section: Buprenorphine Signals Through the Nociception Opioid Peptidementioning

confidence: 99%

Buprenorphine exposure alters the development and migration of interneurons in the cortex

Nieto‐Estévez

Donegan

McMahon

et al. 2020

Preprint

View full text Add to dashboard Cite

The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the U.S. suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy. Opioid use during pregnancy has been associated with increased risk of obstetric complications and adverse neonatal outcomes, including neonatal abstinence syndrome. Currently, opioid use disorder in pregnant women is treated with long-acting opioid agonists, including buprenorphine. Although buprenorphine reduces illicit opioid use during pregnancy and improves infant outcomes at birth, few long-term studies of the neurodevelopmental consequences have been conducted. The goal of the current experiments was to examine the effects of buprenorphine on the development of the cortex using fetal brain tissue, 3D brain cultures, and rodent models. First, we demonstrated that we can grow cortical and subpallial spheroids, which model the cellular diversity, connectivity, and activity of the developing human brain. Next, we show that cells in the developing human cortex express the nociceptin opioid (NOP) receptor and that buprenorphine can signal through this receptor in cortical spheroids. Using subpallial spheroids to grow inhibitory interneurons, we show that buprenorphine can alter interneuron development and migration into the cortex. Finally, using a rodent model of prenatal buprenorphine exposure, we demonstrate that alterations in interneuron distribution can persist into adulthood. Together, these results suggest that more research is needed into the long-lasting consequences of buprenorphine exposure on the developing human brain.

show abstract

Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

Cited by 19 publications

References 24 publications

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

Central N/OFQ-NOP Receptor System in Pain Modulation

Buprenorphine exposure alters the development and migration of interneurons in the cortex

Contact Info

Product

Resources

About