Racemic synthesis and solid phase peptide synthesis application of the chimeric valine/leucine derivative 2-amino-3,3,4-trimethyl-pentanoic acid

• Published in: Pharmazie Vol. 69; no. 7; pp. 496 - 499
• Main Authors: Pelà, Zoppo, L. Del, Allegri, Marzola, Trapella, Ruzza, Calo, Perissutti, Frecentese, Salvadori, Guerrini
• Format: Journal Article
• Language: English
• Published: ESCHBORN Govi-Verlag 01.07.2014; Govi-Verlag Pharmazeutischer Verlag Gmbh
• Subjects: Animals; Calcium - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromatography, High Pressure Liquid; Copper; HEK293 Cells; Humans; Indicators and Reagents; Leucine - chemistry; Life Sciences & Biomedicine; Mice; Pentanoic Acids - chemistry; Peptides - chemical synthesis; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Solid-Phase Synthesis Techniques; Stereoisomerism; Structure-Activity Relationship; Valine - chemistry; S RECEPTOR ANTAGONISTS; NEUROPEPTIDE-S; POTENT; PHARMACOLOGY; BIOLOGICAL-ACTIVITY; ALPHA-AMINO-ACIDS; PURE
• ISSN: 0031-7144
• DOI: 10.1691/ph.2014.3961

The synthesis of non natural amino acid 2-amino-3,3,4-trimethyl-pentanoic acid (Ipv) ready for solid phase peptide synthesis has been developed. Copper (I) chloride Michael addition, followed by a Curtius rearrangement are the key steps for the Ipv synthesis. The racemic valine/leucine chimeric amino acid was then successfully inserted in position 5 of neuropeptide S (NPS) and the diastereomeric mixture separated by reverse phase HPLC. The two diastereomeric NPS derivatives were tested for intracellular calcium mobilization using HEK293 cells stably expressing the mouse NPS receptor where they behaved as partial agonist and pure antagonist.