Multifunctional Opioid Ligands

Anand, Jessica P.; Montgomery, Dan

doi:10.1007/164_2018_104

Cited by 28 publications

(34 citation statements)

References 140 publications

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“…Mice place conditioned with either isomer demonstrated no significant preference or aversion for their respective drug-paired chamber. These results are consistent with earlier tests of multifunctional macrocyclic tetrapeptides [ 9 , 19 ] and could reflect the counteracting effects of agonism at multiple opioid receptors such as MOR and KOR [ 9 , 10 ]. In contrast to 5 , isomer 3 did not demonstrate significant MOR-mediated agonism, but rather KOR- and DOR-mediated antinociception.…”

Section: Discussionsupporting

confidence: 92%

“…Co-administration of either KOR [ 6 , 7 ] or DOR [ 8 ] agonists enhanced the antinociceptive effects of MOR-selective agonists. Some multifunctional opioids also produce reduced side effects [ 9 ], a profile attributed to simultaneous modulation of more than one opioid receptor that may counter their individual adverse effects [ 10 ]. For example, KOR agonism offsets MOR-mediated reinforcement [ 11 ] and respiratory depression [ 12 ], while DOR antagonism may slow the development of MOR agonist analgesic tolerance [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

et al. 2020

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The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

et al. 2020

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“…The recent development of multifunctional agonists targeting opioid and other neuropeptide receptors has been considered as a prospective approach in the separation of their antinociceptive activity from opioid-related side effects like constipation. 34 We recently designed and synthesized a multifunctional agonist DN-9, which simultaneously exhibited agonistic properties at MOP, DOP, KOP, NPFF 1 , and NPFF 2 receptors in the cAMP functional assay. 18 Furthermore, DN-9 produced potent antinociceptive effects in different pain models with minimal side effects.…”

Section: Discussionmentioning

confidence: 99%

Central and peripheral modulation of gastrointestinal transit in mice by DN‐9, a multifunctional opioid/NPFF receptor agonist

Guo

Zhang

et al. 2020

Neurogastroenterology Motil

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Background The nonapeptide DN‐9 functions as a multifunctional agonist to opioid and neuropeptide FF (NPFF) receptors and exhibits antinociceptive effects at the central and peripheral levels. Methods The effects of DN‐9 on small and colonic intestinal transit were evaluated using the upper gastrointestinal (GI) transit test and colonic bead expulsion assay, respectively. Opioid and NPFF receptor antagonists were used to investigate the mechanisms of DN‐9‐induced GI inhibition. Furthermore, the agonism of the DN‐9 analog [Phg9]‐DN‐9 to opioid and NPFF receptors was tested by the cAMP assay. Key results Intracerebroventricular administration of DN‐9 dose‐dependently slowed upper GI transit and colonic expulsion via mu‐ and kappa‐opioid receptors in the brain, independent of the delta‐opioid receptor. Similarly, intraperitoneal injection of DN‐9 dose‐dependently inhibited GI propulsion via the peripheral opioid receptors. DN‐9‐induced GI transit inhibitions were significantly aggravated by the NPFF receptor antagonist RF9. Moreover, the DN‐9 analog [Phg9]‐DN‐9, an agonist at mu‐, delta‐, and kappa‐opioid receptors but not NPFF receptors, inhibited GI more potently than DN‐9. In addition, intracerebroventricular NPFF significantly attenuated the central inhibitory effects induced by [Phg9]‐DN‐9 and morphine. However, central and peripheral injections of NPFF or RF9 almost had no significant effects on GI transit by itself. Conclusion and Inferences Intracerebroventricular and intraperitoneal administrations of DN‐9 inhibit GI transit via opioid receptors in mice by central and peripheral mechanisms, respectively. In addition, the NPFF agonism of DN‐9 possesses antiopioid effects on GI transit, which might explain the reduced constipation at the antinociceptive doses.

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“…Consistent with this, nalbuphine, a κ‐ and μ‐opioid receptor agonist, demonstrates similar analgesic efficacy to morphine, but with negligible respiratory effects (Miller, 1980; Schmidt et al, 1985). Likewise, the addition of μ‐opioid receptor agonist activity might improve the therapeutic utility of κ‐opioid agonists by mitigating dysphoric effects (Anand & Montgomery, 2018).…”

Section: Introductionmentioning

confidence: 99%

Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine‐seeking behaviour

Brice‐Tutt

Wilson

Eans

et al. 2020

British J Pharmacology

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Background and Purpose: The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) is a multifunctional μ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-D-Phe], would demonstrate multifunctional μ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective μ-opioid receptor agonists, while preventing both drug-and stress-induced reinstatement of morphine-induced CPP. Experimental Approach: The opioid receptor agonist and antagonist activity of cyclo [Pro-Sar-Phe-D-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55 C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-D-Phe] to block morphine-and stress-induced reinstatement of extinguished CPP was determined. Key Results: cyclo[Pro-Sar-Phe-D-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED 50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mgÁkg −1 i.p., mediated by μand κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-D-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-D-Phe] prevented stress-and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner.

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Multifunctional Opioid Ligands

Cited by 28 publications

References 140 publications

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

Central and peripheral modulation of gastrointestinal transit in mice by DN‐9, a multifunctional opioid/NPFF receptor agonist

Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine‐seeking behaviour

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