Gabapentin 1-(aminomethyl)cyclohexane acetic acid (Gbp, also known as Neurontin), a structural analog of g-aminobutyric acid (GABA), is effectively utilized for the treatment of neuropathic pain, however, it undergoes facile intramolecular cyclization to form the toxic five-membered cyclic lactam 2-aza-spiro[4,5]decan-3-one.To stabilize conformationally constrained gabapentin, we carried out the construction of small peptidomimetics by N-acylation of Gbp with carbonyl activated N-protected amino acids and small peptides to acheive Cbz-L-Val-Gbp-OH, Cbz-L-Ala-Gbp-OH, Boc-L-Ala-L-Phe-Gbp-OH, Cbz-Gly-L-Ala-bAla-Gbp-OH.Treatment of N-Boc-protected Gbp with L-valine methyl ester, L-pnehyl-L-tryptophan methyl ester and benzylamine gave Gbp conjugates. Analogous reaction was performed between N-Boc-Gbp and L-menthol, cholesterol, thiophenol and cysteinyl L-phenylalanine methyl ester.Gbp conjugates were evaluated for binding the human capsaicin receptor (TrpV1) by homology modeling and molecular docking. These data suggest that novel Gbp conjugates may bind TrpV1 and inhibit its function in the sensation of pain without toxic effects that result from cyclization.

Gabapentin hybrid peptides and bioconjugates synthesis and study of their interaction with TRPV1

245th National Meeting (2013)

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