Identification of potent phenyl imidazoles as opioid receptor agonists

Breslin, Henry J.; Cai, Chaozhong; Miskowski, Tamara A.; Coutinho, Santosh V.; Zhang, Sui‐Po; Hornby, Pamela J.; He, Wei

doi:10.1016/j.bmcl.2006.01.082

Cited by 27 publications

(20 citation statements)

References 5 publications

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“…Therefore, we tested whether blockade of δ opioid receptors modulates the inhibitory effects of µ opioid receptor agonists on the GI tract. We used combinations of reference compounds and selected a molecule from a series of potent phenylimidazoles (Breslin et al ., 2006) that is a mixed µ opioid receptor agonist and δ opioid receptor antagonist (MuDelta). The synthesis and structure of MuDelta are reported separately (Breslin et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist

Wade

Palmer

McKenney

et al. 2012

British J Pharmacology

113

127

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BACKGROUND & PURPOSELoperamide is a selective m opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating m opioid receptor agonism with d opioid receptor antagonism, by combining reference compounds or using a novel compound ('MuDelta'), could normalize GI motility without constipation. EXPERIMENTAL APPROACHMuDelta was characterized in vitro as a potent m opioid receptor agonist and high-affinity d opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic d opioid receptor immunoreactivity was quantified. KEY RESULTSd Opioid receptor antagonism opposed m opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated d opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model. CONCLUSIONS AND IMPLICATIONSMuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.

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Section: Introductionmentioning

confidence: 99%

Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist

Wade

Palmer

McKenney

et al. 2012

British J Pharmacology

113

127

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“…The synthesis and structure of eluxadoline [113] was the culmination of chemical efforts to discover mixed OR subtype modulators that act locally in the intestine [114]. Pharmacokinetic studies in rats, mice and primates demonstrated that eluxadoline has low systemic exposure after oral administration, which is consistent with a local site of action of the compound.…”

Section: Dual or Modulatorsmentioning

confidence: 94%

Drug discovery approaches to irritable bowel syndrome

Hornby

2015

Expert Opinion on Drug Discovery

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Challenges for new drug discovery are the unknown mechanisms underlying IBS, making it difficult to predict clinically efficacious molecular targets, limited options for translational research and disease progression biomarkers. Drugs acting locally via multiple targets (e.g., eluxadoline [The U.S. Food and Drug Administration approved Viberzi (eluxadoline) for IBS-D on May 27th 2015], crofelemer) to validated mechanisms are proving successful with tolerable safety margins. Novel mechanisms, identified and optimized based on the emerging role of nutrient signaling, probiotics or microbial products, are promising. Therapeutic treatment earlier in disease progression may improve response and have longer term benefits.

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“…Appropriately substituted imidazoles were used as CB1 cannabinoid receptor antagonists 7 , modulators of P-glycoprotein (P-gp) mediated multidrug resistance (MDR) 8 and glucagon receptors 9 . The imidazole core was reported to exhibit antiedema and anti-inflammatory 10,11 , analgesic 13 , antifungal 12 , antiviral 14 , anthelmintic 15 , antibacterial 16 , antitumor 17 , antitubercular 18 , antibiotic, anti-ulcerative 19 . The potency and pertinence of imidazole pharmacophore is largely due to its hydrogen bond forming nature as well as its high affinity towards metals like Fe, Zn, and Mg in the protein active sites 20 .…”

Section: Introductionmentioning

confidence: 99%

An Efficient, Solvent Free One Pot Synthesis of Tetra substitue dimidazoles Catalyzed by Nanocrystalline γ-alumina

Shelke¹,

Rajbhoj²,

Nimase³

et al. 2016

Orient. J. Chem

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γ-Alumina nanoparticles (γ-Al 2 O 3 NPs) have been successfully synthesized by electrochemical reduction method. The aqueous solution of tetrapropylammonium bromide was used as an electrolyte cum stabilizer. To prevent spontaneous agglomeration and control nanoparticles size various parameter such as current density, distance between electrodes and concentrations of electrolyte are optimized. γ-Al 2 O 3 NPs thus synthesized were characterized by sophisticated analytical techniques including X-ray diffraction, scanning electron microscopy, energy dispersive spectrophotometer and high-resolution transmission electron microscopy These synthesized γ-Al 2 O 3 NPs were tested used as a catalyst for one pot synthesis of tetraaryl imidazole derivatives from the cyclodehydration and condensation of benzil, aromatic aldehyde, anilines and ammonium acetate under solvent free condition. This method has various advantages like convenient work-up procedure, environmentally benign and less reaction times along with excellent yields. Easy availability, several times recyclability, very simple isolation and eco-friendliness were some attractive features of the nanocrystalline γ-Al 2 O 3 catalyst.

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Identification of potent phenyl imidazoles as opioid receptor agonists

Cited by 27 publications

References 5 publications

Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist

Modulation of gastrointestinal function by MuDelta, a mixed µ opioid receptor agonist/ µ opioid receptor antagonist

Drug discovery approaches to irritable bowel syndrome

An Efficient, Solvent Free One Pot Synthesis of Tetra substitue dimidazoles Catalyzed by Nanocrystalline γ-alumina

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