Pregabalin peptides: conformational comparison of γ3- and γ4-substituted γ-amino acids in αγααα pentapeptides
2019
Basuroy, Krishnayan | Kantharaju, Kamanna | Aravinda, Subrayashastry | Shamala, Narayanaswamy | Balaram, Padmanabhan
Gamma-aminobutyric acid (GABA, gammaAbu), an unsubstituted gamma-amino acid, is an important inhibitory neurotransmitter in the mammalian brain. The role of GABA in the treatment of epilepsy has triggered a great deal of interest in substituted gamma-amino acids, which may serve as GABA analogs, acting as inhibitors of GABA aminotransferase. Pregabalin (Pgn), a well-known antiepileptic drug, is also a beta-substituted gamma3-amino acid. Pregabalin and gamma4Leu, an isomer of the pregabalin (Pgn) residue, both carrying the same isobutyryl group in the side chain, were introduced in the present study to have a comparison of their respective conformational differences as well as their role in influencing the overall conformation of the peptides, they are inserted in. Two alpha–gamma–alpha–alpha–alpha hybrid pentapeptides were designed that contain Aib-Pgn and Aib-gamma4Leu segments at the N terminus. The study provides a detailed analysis of the conformational properties and non-covalent interactions observed in the crystal structures of two polymorphs of the pentapeptide monohydrate, Boc-Aib-(S)Pgn-Leu-Phe-Val-OMe (C₃₈H₆₃N₅O₈·H₂O) and the isomeric pentapeptide, Boc-Aib-gamma4(R)Leu-Leu-Phe-Val-OMe (C₃₈H₆₃N₅O₈), obtained from single crystal X-ray diffraction experiments.
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