Hybrid Peptide Design. Hydrogen Bonded Conformations in Peptides Containing the Stereochemically Constrained γ-Amino Acid Residue, Gabapentin

Abstract

The crystal structure of 12 peptides containing the conformationally constrained 1-(aminomethyl)cyclohexaneacetic acid, gabapentin (Gpn), are reported. In all the 39 Gpn residues conformationally characterized so far, the torsion angles about the C^α−C^β and C^β−C^γ bonds are restricted to the gauche conformation (±60°). The Gpn residue is constrained to adopt folded conformations resulting in the formation of intramolecularly hydrogen-bonded structures even in short peptides. The peptides Boc-Ac₆c-Gpn-OMe 1 and Boc-Gpn-Aib-Gpn-Aib-OMe 2 provide examples of C₇ conformation; peptides Boc-Gpn-Aib-OH 3, Boc-Ac₆c-Gpn-OH 4, Boc-Val-Pro-Gpn-OH 5, Piv-Pro-Gpn-Val-OMe 6, and Boc-Gpn-Gpn-Leu-OMe 7 provide examples of C₉ conformation; peptide Boc-Ala-Aib-Gpn-Aib-Ala-OMe 8 provides an example of C₁₂ conformation and peptides Boc-βLeu-Gpn-Val-OMe 9 and Boc-βPhe-Gpn-Phe-OMe 10 provide examples of C₁₃ conformation. Gpn peptides provide examples of backbone expanded mimetics for canonical α-peptide turns like the γ (C₇) and the β (C₁₀) turns. The hybrid βγ sequences provide an example of a mimetic of the C₁₃ α-turn formed by three contiguous α-amino acid residues. Two examples of folded tripeptide structures, Boc-Gpn-βPhe-Leu-OMe 11 and Boc-Aib-Gpn-βPhg-NHMe 12, lacking internal hydrogen bonds are also presented. An analysis of available Gpn residue conformations provides the basis for future design of folded hybrid peptides.