Studies on the molecular mechanism of thrombin receptor activation by means of ligand peptides containing a series of fluorinated phenylalanines

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The receptor of serine protease thrombin is a novel type of receptor, in which the peptite ligand is present in the N-terminal portion of the receptor itself. It was found that the receptor can be activated by the synthetic peptide Ser-Phe-Leu-Leu-Arg-Asn-Pro (SFLLRNP) without thrombin, and that Phe-2 of this peptide is crucially important to the receptor. recognition and activation. The aim of the present study is to clarify the interaction mode between Phe-2-phenyl and thrombin receptor aromatic groups. There are two possibilities for interaction of the ligand Phe-phenyl group : i.e., pi-pi stacking interaction and CH/pi interaction. To differentiate these interactions, we have incorporated a series of fluorinated phenylalanines. Fluorine is the most electronegative atom, the size of which is almost the same as hydrogen. It was immediately recognized that the fluorine substitution is allowed ony at the para-position. The derivative with pentafluorophenylalanine was totally devoid of … More activity. These results suggested that Phe-2 requires hydrogen atom(s) on the benzene ring presumably for interaction with the receptor. No activity enhancement observed for analogs with para-chloro-, bromo-, or iodophenylalanine indicated the importance of a high electronegativity of fluorine to intensify a dipole of CH(s) remaining in the Phe-2-benzenering, and suggested the presence of face-to-edge pi-pi interaction. Reduced but full activation by the derivative of 3,4,5-trifluorophenylalanine marked a hydrogen at position 6 as a structural element for direct interaction with the receptor aromatic ring. When strongly meta-orienting the trifluoromethyl group was introduced, only the derivative of 3-trifluoromethylpehnylalanine was fully active. All these results indicated that hydrogens at position 5 and 6 are the most important structural element for receptor interaction and that the interaction of Phe-2 of SFLLRNP appeared to be a face-to-edge pi-pi interaction based upon the CH/pi interaction between the Phe-2-phenyl group and the receptor aromatic group. Less