Highly Potent and Selective New Diphenethylamines Interacting with the κ-Opioid Receptor: Synthesis, Pharmacology, and Structure–Activity Relationships

Erli, Filippo; Guerrieri, Elena; Haddou, Tanila Ben; Lantero, Aquilino; Mairegger, Michael; Schmidhammer, Helmut; Spetea, Mariana

doi:10.1021/acs.jmedchem.7b00981

Cited by 28 publications

(35 citation statements)

References 42 publications

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“…The pharmacological profile of HS665 matched RB64. Another study from the same group focused on the development of novel derivatives based on the same structural scaffold and expanded the structure-activity relationships (SARs) of the original series [ 73 ]. In this study, HS665 and HS666 pharmacology was studied subcutaneously in CD1 mice.…”

Section: Kor Biased Agonismmentioning

confidence: 99%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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Section: Kor Biased Agonismmentioning

confidence: 99%

Biased Opioid Ligands

2020

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“…When injected systemically (intraperitoneally) HS665 (although named MCBPHA in this paper) produced modest motor incoordination in male C57BL/6 mice in the rotarod assay, which was similar to MCPPHA (which was compound 3 in Spetea et al, 2012), but less than U50,488 (Dunn et al, 2018). A library of derivatives of HS665 and HS665 were synthesized with several compounds showing subnanomolar affinity and exceptional κOR selectivity, as well as high G-protein potency acting as either full or partial agonists (Erli et al, 2017). While those new derivatives were not assessed for β-arrestin recruitment, the new derivatives displayed increased antinociceptive potencies compared with U50,488, HS665 and HS666 in the acetic acid-induced writhing test (Erli et al, 2017).…”

Section: G-protein Biased Kappa Agonistsmentioning

confidence: 99%

“…A library of derivatives of HS665 and HS665 were synthesized with several compounds showing subnanomolar affinity and exceptional κOR selectivity, as well as high G-protein potency acting as either full or partial agonists (Erli et al, 2017). While those new derivatives were not assessed for β-arrestin recruitment, the new derivatives displayed increased antinociceptive potencies compared with U50,488, HS665 and HS666 in the acetic acid-induced writhing test (Erli et al, 2017). Another derivative of the trialkylamine scaffold, BPHA (compound 5 in Spetea et al, 2012), did not measurably recruit β-arrestin 2 as determined using the PathHunter cell assay using U50,488 as reference compound (Table 1) and did not cause locomotor incoordination (Dunn et al, 2018).…”

Section: G-protein Biased Kappa Agonistsmentioning

confidence: 99%

A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

Cummins²,

Cassell

et al. 2019

Front. Pharmacol.

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Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), N-n -butyl- N -phenylethyl- N -3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6′GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response.

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“…Antinociception was assessed 20 min after POMO s.c. injection using the hot-plate assay. Doses and pretreatment times of the antagonists were chosen based on pilot studies and previous research ( Lattanzi et al, 2002 ; Erli et al, 2017 ). Antinociceptive response was expressed as maximum possible effect (%MPE), calculated according to the equation: %MPE = (test latency - basal latency)/(cut-off - basal latency) × 100.…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa-Opioid Receptor Agonist With Reduced Constipation in Mice

et al. 2018

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Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in pain control are to provide analgesia of adequate efficacy and to reduce complications associated with the currently available drugs. Opioids are the mainstay for the treatment of moderate to severe pain. However, opioid pain medications also cause detrimental side effects, thus highlighting the need of innovative and safer analgesics. Opioids mediate their actions via the activation of opioid receptors, with the mu-opioid receptor as the primary target for analgesia, but also for side effects. One long-standing focus of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects. In this study, we describe the in vitro and in vivo pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and functional activity, and in vivo behavioral properties (nociception and gastrointestinal motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse vas deferens bioassays, POMO was a highly efficacious and full agonist, being more potent than 14-OMO. In the [35S]GTPγS binding assays with membranes from CHO cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective in acute thermal nociception (hot-plate test, AD50 = 0.7 nmol/kg) in mice after subcutaneous administration, with over 70- and 9000-fold increased potency than 14-OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa-opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses.

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Highly Potent and Selective New Diphenethylamines Interacting with the κ-Opioid Receptor: Synthesis, Pharmacology, and Structure–Activity Relationships

Cited by 28 publications

References 42 publications

Biased Opioid Ligands

Biased Opioid Ligands

A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa-Opioid Receptor Agonist With Reduced Constipation in Mice

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