Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation

Iguchi, Yusuke; Nishimaki-Mogami, Tomoko; Yamaguchi, Masafumi; Teraoka, Fumiteru; Kaneko, Tetsuo; Une, Mizuho

doi:10.1248/bpb.34.1

Cited by 36 publications

(27 citation statements)

References 28 publications

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“…Second, OA -a potent TGR5 agonist that does not activate nuclear BA receptors (48) -was the strongest stimulant of excitability. Third, UDCA -which does not activate TGR5 or is a weak agonist (28,49), yet retains the irritant and detergent properties of BAs -had no effect on neuronal excitability at any concentration tested. The effects of DCA, TLCA, and OA on rheobase were concentration dependent, and, with the exception of TLCA, all agonists increased AP discharge frequency at the highest tested concentrations.…”

Section: Discussionmentioning

confidence: 95%

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The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

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Patients with cholestatic disease exhibit pruritus and analgesia, but the mechanisms underlying these symptoms are unknown. We report that bile acids, which are elevated in the circulation and tissues during cholestasis, cause itch and analgesia by activating the GPCR TGR5. TGR5 was detected in peptidergic neurons of mouse dorsal root ganglia and spinal cord that transmit itch and pain, and in dermal macrophages that contain opioids. Bile acids and a TGR5-selective agonist induced hyperexcitability of dorsal root ganglia neurons and stimulated the release of the itch and analgesia transmitters gastrin-releasing peptide and leucineenkephalin. Intradermal injection of bile acids and a TGR5-selective agonist stimulated scratching behavior by gastrin-releasing peptide-and opioid-dependent mechanisms in mice. Scratching was attenuated in Tgr5-KO mice but exacerbated in Tgr5-Tg mice (overexpressing mouse TGR5), which exhibited spontaneous pruritus. Intraplantar and intrathecal injection of bile acids caused analgesia to mechanical stimulation of the paw by an opioid-dependent mechanism. Both peripheral and central mechanisms of analgesia were absent from Tgr5-KO mice. Thus, bile acids activate TGR5 on sensory nerves, stimulating the release of neuropeptides in the spinal cord that transmit itch and analgesia. These mechanisms could contribute to pruritus and painless jaundice that occur during cholestatic liver diseases.

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Section: Discussionmentioning

confidence: 95%

“…tic activity, while retaining the detergent and irritant properties of BAs (28,49). UDCA (30 or 100 μM, 10 minutes) did not affect rheobase, AP discharge frequency, resting membrane potential, or input resistance ( Figure 4E and data not shown).…”

Section: Figurementioning

confidence: 89%

The TGR5 receptor mediates bile acid–induced itch and analgesia

et al. 2013

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“…Likewise, UDCA derivatives bearing a methyl group at the C3 position (23, 24) proved to be less active than the parent compound (Table 10.2). 56 Secondly, while the oxidation of the 3a-hydroxyl group led to the enhancement of the activity in CDCA (3) and LCA (1), its elimination or epimerization decreased the potency of the compound at the receptor (Table 10.2). 5 Interestingly, a different trend was observed in the case of UDCA derivatives, with either the epimerization or the oxidation proving detrimental for TGR5 agonist activity.…”

Section: Steroidal Ligands: Bile Acids Bile Alcohols and Derivativesmentioning

confidence: 99%

“…5 Interestingly, a different trend was observed in the case of UDCA derivatives, with either the epimerization or the oxidation proving detrimental for TGR5 agonist activity. 56 The authors ascribed this discrepancy to the presence of the 7b-hydroxyl group that might promote a different binding mode of the 3-dehydro-UDCA (25) to the receptor. The study of Sato et al showed that the introduction of alkyl groups in C7-b position of CDCA improved TGR5 agonist activity, with the potency being directly correlated with the size of the substituent (Table 10.2).…”

Section: Steroidal Ligands: Bile Acids Bile Alcohols and Derivativesmentioning

confidence: 99%

Chapter 10. TGR5 Agonists in Development

Macchiarulo¹,

Gioiello²,

Pellicciari³

2012

Drug Discovery

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Lipid receptors are a growing family of druggable targets that include cell surface receptors and ligand-dependent transcription factors. 1 They mediate a plethora of signaling pathways involved in the fine tuning of important physiological functions such as the control of metabolism, organ physiology, cell differentiation, and homeostasis. As a consequence, small-molecule drug development for lipid receptors is attracting a great deal of interest in academia and pharmaceutical companies.TGR5, also known as M-BAR, AXOR109, BG37, or GPR131, is a membrane lipid receptor activated by bile acids (BAs) and G-protein coupled to the production of cAMP. The activation of TGR5 bestows on BAs the ability to modulate non-genomic signaling pathways that complement their genomic actions mostly mediated by the interaction with the nuclear receptor FXR. 2 Major non-genomic actions of BAs include immunosuppressive properties and the regulation of glucose metabolism as well as energy homeostasis. 3 While the therapeutic relevance of the immune properties of TGR5 activation is pending further appraisals, the effect of the receptor on glucose metabolism and energy homeostasis have thrust TGR5 into the limelight as an attractive therapeutic target in the arena of metabolic disorders, including type 2 diabetes (T2D) and obesity.

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“…Structurally, TGR5 agonists can fall into two categories. The first category is bile acid derivatives, [10][11][12] such as lithocholic acid (LCA) and 6α-ethyl-23(S)-methylcholic acid (INT-777). The second category is non-bile acid derivatives, including naturally occurring non-bile acid agonists such as oleanolic acid and betulinic acid, 13,14) and synthetic small molecular TGR5 agonists.…”

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confidence: 99%

Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

et al. 2016

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A novel therapy that stimulates endogenous glucagon-like peptide-1 (GLP-1) secretion by Takeda G-protein-coupled receptor 5 (TGR5) agonists might be a superior alternative for the treatment of type 2 diabetes mellitus. A series of 4-phenoxythiazol-5-carboxamides were developed as highly potent TGR5 agonists using a bioisosteric replacement strategy based on the scaffold of 4-phenoxynicotinamides. The structure-activity relationship on the bottom phenyl ring and the thiazole ring was extensively studied, and the 2-methylthiazole derivatives 30c and e displayed the best in vitro potency toward human TGR5, with EC 50 values of approximately 1 nM. While endowed with excellent in vitro potency, the 2-methyl-thiazoles were flawed with high microsomal clearance.Key words Takeda G-protein-coupled receptor 5 agonist; bioisostere; microsomal clearance; structureactivity relationship Takeda G-protein-coupled receptor 5 (TGR5), also known as G-protein coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor responsive to bile acids. It has been found to be ubiquitously expressed in animal and human tissues, including the liver, intestine, heart, spleen, skeletal muscle, brown adipose tissue, gallbladder and brain. [1][2][3][4] It is thought to play an important role in the regulation of energy homeostasis and glucose metabolism. Activation of the TGR5 receptor by bile acids triggers an increase in energy expenditure in brown adipose tissue and skeletal muscle.5) More importantly, TGR5 activation also promotes glucagon-like peptide-1 (GLP-1) secretion in the intestine. 6) As a member of the incretin family, GLP-1 acts as an important physiological regulator in glucose control via several mechanisms of action.7) But endogenous GLP-1 is significantly limited as a direct drug for the treatment of type 2 diabetes because of its rapid inactivation in plasma by dipeptidyl peptidase-4 (DPP-4). There are two main classes of alternative GLP-1-based drugs being widely used in a clinical setting: DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. 8) However, these drugs may not be able to halt the progression of type 2 diabetes because they all exert their actions through increasing the plasma concentration of "GLP-1R agonists," and they thus may lack some of the local actions that endogenous GLP-1 is likely to have. 9)Therefore, a novel therapy that stimulates endogenous GLP-1 secretion by TGR5 agonists is considered as a superior alternative for the treatment of type 2 diabetes mellitus.In recent years, many different kinds of TGR5 agonists have been reported (Fig. 1). Structurally, TGR5 agonists can fall into two categories. The first category is bile acid derivatives, [10][11][12] such as lithocholic acid (LCA) and 6α-ethyl-23(S)-methylcholic acid (INT-777). The second category is non-bile acid derivatives, including naturally occurring non-bile acid agonists such as oleanolic acid and betulinic acid, 13,14) and synthetic small molecular TGR5 agonists. [15][16][17][18][19][20][21][22] However, only one ...

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Effects of Chemical Modification of Ursodeoxycholic Acid on TGR5 Activation

Cited by 36 publications

References 28 publications

The TGR5 receptor mediates bile acid–induced itch and analgesia

The TGR5 receptor mediates bile acid–induced itch and analgesia

Chapter 10. TGR5 Agonists in Development

Discovery and Structure–Activity Relationship Study of 4-Phenoxythiazol-5-carboxamides as Highly Potent TGR5 Agonists

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