title: Discovery of dipeptides with high affinity to the specific binding site for substance P1-7.
abstract: Substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is the major bioactive metabolite of substance P. The interest in this heptapeptide originates from the observation that it modulates, and in certain cases opposes the effects of the parent peptide, e.g., the nociceptive effect. The mu-opioid receptor agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH(2)) has been found to also interact with the specific binding site of SP(1-7) with only a 10-fold lower affinity compared to the native peptide. Considering the smaller size of EM-2 compared to the target heptapeptide, it was selected as a lead compound in the development of low-molecular-weight ligands to the SP(1-7) binding site. An alanine scan and truncation study led to the unexpected discovery of the dipeptide H-Phe-Phe-NH(2) (K(i) = 1.5 nM), having equal affinity as the endogenous heptapeptide SP(1-7.) Moreover, the studies show that the C-terminal phenylalanine amide is crucial for the affinity of the dipeptide.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fransson
authors.forename: Milad
authors.initials: M
authors.lastname: Botros
authors.forename: Christian
authors.initials: C
authors.lastname: Sköld
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: Mathias
authors.initials: M
authors.lastname: Hallberg
authors.forename: Anja
authors.initials: A
authors.lastname: Sandström
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013373:Substance P / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D013373:Substance P; C036877:substance P (1-7)