A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

Bao, Xiaofeng; Liu, Duliang; Jin, Yanyan; Yang, Yao

doi:10.3390/molecules171214288

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…Opioid receptors have been shown to be present on peripheral sensory nerve terminals, and their expression is upregulated in inflamed tissues. − Significantly, overexpression of DOR in keratinocytes compromises the proteins essential to the integrity of the skin barrier, and MOR activation promotes wound healing via regulation of cytokeratin 16 and TGF-β type II receptor expression in keratinocytes . FBNTI, the bivalent ligand MDAN-21, and the peripherally restricted MOR agonist, loperamide (Imodium), were evaluated topically by application to the Complete Freund’s Adjuvant (CFA-inflamed left hind paw) of ICR-CD1 mice in a 50% ethanol vehicle, and antihyperalgesia was assessed using the Hargreaves radiant heat assay (Figure ). By this route of administration, FBNTI and MDAN-21 were equipotent at producing antihyperalgesia.…”

Section: Resultsmentioning

confidence: 99%

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

et al. 2020

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This report describes the unique pharmacological profile of FBNTI, a potent DOR antagonist that acts as a MOR agonist via an allosteric mechanism. Binding of FBNTI to opioid receptors expressed in HEK 293 cells revealed a 190-fold greater affinity for DOR (K i = 0.84 nM) over MOR (K i = 160 nM). In mice, intrathecal FBNTI produced potent antinociception (ED50 = 46.9 pmol/mouse), which was antagonized by selective MOR antagonists (CTOP, β-FNA). Autoantagonism of the MOR agonism by FBNTI was observed above the ED75 dose, suggesting antagonism of activated MOR. That FBNTI is devoid of agonism in DOR knockout mice is consistent with allosteric activation of the MOR protomer via FBNTI bound to within a MOR–DOR heteromer. This proposed mechanism is supported by calcium mobilization assays, which indicate that FBNTI selectively activates the MOR–DOR heteromer and functionally antagonizes the MOR protomer at >ED75. The unprecedented mode of MOR activation by FBNTI may be responsible for the lack of tolerance after intrathecal (i.t.) administration. FBNTI was highly effective upon topical administration to the ipsolateral hind paw in the Hargreaves assay (EC50 = 0.17 ± 0.08 μM) and without significant contralateral activity, suggesting a lack of systemic exposure.

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Section: Resultsmentioning

confidence: 99%

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

et al. 2020

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“…The inhibitory effect of the compound on AA-induced diarrhea at a dose of 25 mg/kg was 75.0 ± 2.3%, which was similar to that observed with loperamide at doses of 2.5 mg/kg (77.8 ± 4.5%) (Table 3). 19-Deoxyicetexone produced a significant inhibition of AA-induced diarrhea but this compound had no effect on PGE 2 -induced diarrhea, suggesting that 19-deoxyicetexone inhibited the release of prostaglandins [15] and that this diterpenoid shows affinity and selectivity for the opioid receptor [16].…”

Section: Resultsmentioning

confidence: 99%

Antidiarrheal Activity of 19-Deoxyicetexone Isolated from Salvia ballotiflora Benth in Mice and Rats

et al. 2013

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Abstract:The antidiarrheal properties of 19-deoxyicetexone, a diterpenoid isolated from Salvia ballotiflora were evaluated on castor oil-, arachidonic acid (AA)-and prostaglandin (PGE 2 )-induced diarrhea in rodent models. The structure of 19-deoxyicetexone was determined by X-ray crystallography, mass spectrometry (EI-MS), as well as ultraviolet (UV-Vis), infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopies. This compound significantly and dose-dependently reduced frequency of stooling in castor oil-induced diarrhea, and at dose of 25 mg/kg it also inhibited diarrhea induced with AA, while it had no effect on PGE 2 -induced diarrhea. This compound at doses of 25 mg/kg also diminished castor oil-induced enteropooling and intestinal motility, and inhibited the contraction of the rats' ileum induced by carbachol chloride at a concentration of 100 µg/mL. 19-Deoxyicetexone did not present acute toxicity at doses of 625 mg/kg. Its antidiarrheal activity may be due to increased reabsorption of NaCl and water and inhibition of the release of prostaglandins, gastrointestinal motility and fluid accumulation in the intestinal tracts of rats. These findings suggest that 19-deoxyicetexone may be used in the treatment of diarrhea, although more studies must be carried out to confirm this.

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“…1 H NMR (400 MHz, CDCl 3 ): δ 13.12 (s, 1H), 9.11 (s, 1H), 7.80 (dd, J = 5.4, 3.0 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.26−7.15 (m, 1H), 3.96−3.78 (m, 5H), 3.72 (m, J = 14.0 Hz, 4H), 3.57 (br s, 1H), 3.48 (br s, 1H), 3.26 (br s, 2H), 2.66−2.51 (m, 3H), 2.22 (dt, J = 15.0, 7.6 Hz, 1H), 1.99 (tt, J = 13.4, 6.9 Hz, 2H), 1.80− 1.60 (m, 3H), 1.18 (dt, J = 10.7, 7.5 Hz, 3H). (40). Hydrazine (0.2 mL, 50−60% wt in H 2 O) was added to a solution of 39 (310 mg, 0.6 mmol) in EtOH (20 mL), and the solution was stirred at reflux for 3 h. The solvent was removed under vacuum, and the residue was diluted with 20% K 2 CO 3 aq solution and extracted with DCM.…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

“…Due to the limited availability of reported structure–activity relationships (SARs) for dual-target MOR–D 3 R ligands, ,− we used a fragment-based drug design approach, supported by molecular docking, computer-aided drug design (CADD), and extensive in vitro pharmacology to guide SAR, hit optimization, and lead identification.…”

Section: Introductionmentioning

confidence: 99%

Novel Dual-Target μ-Opioid Receptor and Dopamine D₃ Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

et al. 2021

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The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure–activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist–D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.

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A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

Cited by 5 publications

References 23 publications

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

Antidiarrheal Activity of 19-Deoxyicetexone Isolated from Salvia ballotiflora Benth in Mice and Rats

Novel Dual-Target μ-Opioid Receptor and Dopamine D₃ Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

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A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

Cited by 5 publications

References 23 publications

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

Antidiarrheal Activity of 19-Deoxyicetexone Isolated from Salvia ballotiflora Benth in Mice and Rats

Novel Dual-Target μ-Opioid Receptor and Dopamine D3 Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management

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Product

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Novel Dual-Target μ-Opioid Receptor and Dopamine D₃ Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management