α–γ Hybrid Peptides that Contain the Conformationally Constrained Gabapentin Residue: Characterization of Mimetics of Chain Reversals

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Abstract
The crystal structures of four dipeptides that contain the stereochemically constrained γ-amino acid residue gabapentin (1-(aminomethyl)cyclohexaneacetic acid Gpn) are described. The molecular conformation of Piv-Pro-Gpn-OH (1), reveals a β-turn mimetic conformation, stabilized by a ten atom CH⋅⋅⋅O hydrogen bond between the Piv CO group and the pro S hydrogen of the Gpn CH2CO group. The peptides Boc-Gly-Gpn-OH (2), Boc-Aib-Gpn-OH (3), and Boc-Aib-Gpn-OMe (4) form compact, folded structures, in which a distinct reversal of polypeptide chain direction is observed. In all cases, the Gpn residue adopts a gauche,gauche (g,g) conformation about the CγCβ (θ1) and CβCα (θ2) bonds. Two distinct Gpn conformational families are observed. In peptides 1 and 3, the average backbone torsion angle values for the Gpn residue are ϕ=98°, θ1=−62°, θ2=−73°, and ψ=79°, while in peptide 2 and 4 the average values are ϕ=−103°, θ1=−46°, θ2=−49°, and ψ=−92°. In the case of 1 and 3, an intramolecular nine-membered OH⋅⋅⋅O hydrogen bond is formed between the CO of the preceding residue and the terminal carboxylic acid OH group. All four α–γ dipeptide sequences yield compact folded backbone conformations; this suggests that the Gpn residue may be employed successfully in the design of novel folded structures.