Conformational determinants of agonist versus antagonist properties of [D-Pen2,D-Pen5]enkephalin (DPDPE) analogs at opioid receptors. Comparison of X-ray crystallographic structure, solution 1H NMR data, and molecular dynamic simulations of [L-Ala3]DPDPE and [D-Ala3]DPDPE

c-[d-Pen2,d-Pen5]enkephalin (DPDPE, 1) is a cyclic, constrained, highly potent, δ opioid receptor selective peptide agonist. Substitution of Gly3 with l-Ala in DPDPE to give [l-Ala3]DPDPE (2) has been shown to produce a peptide with much greater δ receptor binding selectivity than DPDPE itself. However [l-Ala3]DPDPE is only a partial agonist in in vivo antinociception and actually was found to potently antagonize the antinociceptive effects of DPDPE at δ receptors in the brain. In comparison, [d-Ala3]DPDPE (3) is a weak and poorly selective δ agonist. In an effort to correlate the biological profiles of these peptides with secondary structure, [l-Ala3]DPDPE and [d-Ala3]DPDPE were studied by X-ray crystallography and 1H and 13C NMR in DMSO solution. Crystals of both peptides were obtained using vapor diffusion techniques. [l-Ala3]DPDPE crystallizes in the monoclinic space group C2 with cell dimensions a = 36.35(1) A, b = 19.737(4) A, c = 28.16(1) A, β = 129.07(2)°, and V = 15688(9) A3. The asymmetric unit ...