The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11. Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.
The immunoglobulin (Ig) level in serum from Atlantic cod, Gudus morhua L. (Teleostomi, Gadiformes), was measured using ELISA. Cod serum contains 5.62k0.19 mg Igml I , which constitute 17.2% of the total serum proteins.Polyclonal and monoclonal antibodies (Ab) against cod-Ig were used for cross-reactivity studies in sera from other species. The cross-reaction with polyclonal Ab was high in gadifom fish, and low or absent in the other tested species. Immunoprecipitation showed that the Ab only binds to the Ig of the serum from the other species. The results within the gadiform group indicate that (1) Gadidae and Lotidae are more closely related to each other than to Merluccidae, (2) Phycidae is more distant related to Lotidae than earlier considered, (3) Zoarcidae seem to be more distant related to Gadus than other species of Gadiformes. These results support recent revisions of the systematics of Gadiformes.Monoclonal Ab against the heavy chain of cod-Ig show no, or small (< 15%) cross-reactions with serum from gadiform species. One monoclonal Ab against the light chain shows high crossreaction and also binds to Ig from species outside the Gadiformes, indicating that the light chain of Ig might be more conserved than the heavy chain.
A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
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