Cyclic pentapeptides of chiral sequence DLDDL as scaffold for antagonism of G‐protein coupled receptors: Synthesis,activity and conformational analysis by NMR and molecular dynamics of ITF 1565 a substance P inhibitor

Under the hypotheses of a structurally related binding site for antagonists of G‐protein coupled receptors and the ability of cyclic pentapeptides of chiral sequence D ¹L ²D ³D ⁴L ⁵ to form rigid structures with which probe the pharmacophoric specificity of these receptors, inhibitors of substance P were designed based on available structure–activity relationships. ITF 1565, cyclo[D ‐Trp¹‐Pro²‐D ‐Lys³‐D ‐Trp⁴‐Phe⁵], antagonized substance P activity mediated by type 1 neurokinin receptor (NK1) whereas it acted weakly against NK2 and did not inhibit endothelin at all. The preferential conformation of the peptide was obtained from nmr spectroscopy and computer calculations, and shown to contain the same βII‐turn and γ′‐turn found in other cyclic pentapeptides with the same chiral sequence. The structure of the peptide was compared with that of the β‐D ‐glucose molecule that has been proposed as a semirigid scaffold for antagonists of G‐protein coupled receptors. The γ′‐turn of the cyclic peptide superimposed well with β‐D ‐glucose in the chair conformation. Furthermore, when the side chains were considered, the aromatic groups of the two molecules were found to generally overlap. These results support the view of G‐protein coupled receptors as possessing structurally similar binding sites for antagonists and suggest that cyclic pentapeptides of chiral sequence D ¹L ²D ³D ⁴L ⁵ may be useful as semirigid scaffolds for the design of antagonists of this family of receptors. © 1999 John Wiley & Sons, Inc. Biopoly 50: 211–219, 1999