Simple and efficient solid-phase synthesis of unprotected peptide aldehyde for peptide segment ligation

International audienceWe describe an efficient solid-phase synthesis of C-terminal peptide aldehyde. Making use of the stability of the PAM linker towards both acid and base conditions, a pentapeptide was synthesized starting from a PAM resin according to Fmoc/tBu chemistry. The side-chains were deprotected by TFA. The peptide was cleaved by aminolysis with aminoacetaldehyde-dimethylacetal leading to a C-terminal masked aldehyde. The unprotected peptide aldehyde was then coupled to amino-oxy derivatives by chemoselective ligation in aqueous solution

Microwave-assisted Synthesis of Novel Thiazolocarbazoles and Evaluation as Potential Anticancer Agents. Part III

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Identification and pharmacological properties of E339–3D6, the first nonpeptidic apelin receptor agonist

International audienceApelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, non-peptidic agonists and antagonists of the apelin receptor are required. To identify such compounds which do not exist to date, we used an original Fluorescence Resonance Energy Transfer-based assay to screen a GPCR-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolate E339-3D6 that displayed a 90 nmol/L affinity, behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first non-peptidic agonist of the apelin receptor, the optimization of which will allow to develop a new generation of vasodilator and aquaretic agents

Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

International audienc

Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist

International audienceApelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, nonpeptidic agonists and antagonists of the apelin receptor are required. To identify such compounds that do not exist to date, we used an original fluorescence resonance energy transfer-based assay to screen a G-protein-coupled receptor-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolated E339-3D6 that displayed a 90 nM affinity and behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first nonpeptidic agonist of the apelin receptor, the optimization of which will allow development of a new generation of vasodilator and aquaretic agents

Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339–3D6 (<b>1</b>) was described as the first nonpeptidic apelin receptor agonist. We show here that <b>1</b> is actually a mixture of polymethylated species, and we describe an alternative and versatile solid-phase approach that allows access to highly pure <b>27</b>, the major component of <b>1</b>. This approach was also applied to prepare a series of derivatives in order to identify the crucial structural determinants required for the ligand to maintain its affinity for the apelin receptor as well as its capacity to promote apelin receptor signaling and internalization. The study of the structure–activity relationships led to the identification of ligands <b>19</b>, <b>21</b>, and <b>38</b>, which display an increased affinity compared to that of <b>27</b>. The latter and <b>19</b> behave as full agonists with regard to cAMP production and apelin receptor internalization, whereas <b>21</b> is a biased agonist toward cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (<i>T</i>_1/2 > 10 h) than the endogenous apelin-17 peptide <b>2</b> (<i>T</i>_1/2 < 4 min)