Free fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon‐like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β cells. As these receptors are modulators of nutrient‐stimulated glucose regulation, the aim of this study was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK‐875, AZ423, Metabolex‐36) in mice.

Experimental Approach:

Mouse mucosa was mounted in Ussing chambers, voltage‐clamped and the resultant short‐circuit current (Isc) was recorded continuously. Pretreatments included antagonists of FFA1, Y1 or Y2 receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed in vitro and in vivo.

Key Results:

FFA1 and FFA4 agonism required glucose and reduced Isc in a PYY‐Y1 receptor‐dependent manner. The novel compounds were more potent than GW9508. The FFA1 antagonists (GW1100 and ANT825) blocked FFA1 activity only and revealed FFA1 tonic activity. The FFA4 agonist, Metabolex‐36, slowed colonic transit in vitro but increased small intestinal transit in vivo.

Conclusions and Implications:

The selective FFA1 and FFA4 agonists were more potent at reducing Isc than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY‐stimulated Y1 receptors mediated their responses, which were glucose sensitive, potentially limiting hypoglycaemia. ANT825 revealed tonic activity and the possibility of endogenous FFA1 ligands causing PYY release. Finally, FFA4 agonism induced regional differences in transit.

2013-08-01·International journal of pharmaceutics2区 · 医学

Mucus can change the permeation rank order of drug candidates

2区 · 医学

Article

作者: Maria Elisabeth Due-Hansen ; Elisabeth Christiansen ; Trond Ulven ; Ellen Hagesaether

The aim of the study was to test the effect of mucus on the permeability of newly developed structurally related free fatty acid receptor 1-agonists TUG-488, TUG-499 and TUG-424, which were compared to the more hydrophilic ketoprofen and the more hydrophobic testosterone as reference drugs. The model membrane was cell monolayers consisting of methotrexate treated HT29 cells grown for approximately one, two or three weeks, and thereby differing in the amount of goblet cells and hence mucus. The results show that the permeation of all compounds was high and that mucus in most cases only had a minor influence. However, for one of the drug candidates, TUG-499, mucus had a clear impact, and this could not be explicitly related to the hydrophobicity of this compound. Secreted mucus thus changed the obtained rank order of permeation. This was especially apparent when the experiments were carried out at a lower agitation. These results indicate that an experimental system without mucus can give a faulty rank order of permeation compared to mucous membranes when structurally related drug candidates are tested.

2008-11-27·Journal of medicinal chemistry1区 · 医学

Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA₁/GPR40), a Potential Target for the Treatment of Type II Diabetes

1区 · 医学

Article

作者: Liebscher, Kathrin ; Bond, Andrew D. ; Urban, Christian ; Kassack, Matthias U. ; Christiansen, Elisabeth ; Kostenis, Evi ; Karlsen, Kasper K. ; Ulven, Trond ; Drewke, Christel ; Hamacher, Alexandra ; Ullrich, Susanne ; Spinrath, Andreas ; Merten, Nicole

A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA(1)) has been discovered and explored. The preferred compound 20 (TUG-424, EC(50) = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA(1) in metabolic diseases such as diabetes or obesity.

100 项与 TUG-424 相关的药物交易

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