title: In vitro pharmacological evaluation of the radiolabeled C-terminal substance P analogue Lys-Phe-Phe-Gly-Leu-Met-NH2: Does a specific binding site exist?
abstract: In the present paper, we report the synthesis, radiolabeling and comprehensive pharmacological evaluation of a C-terminally truncated tachykinin derivative, 3H-KFFGLM-NH2. The C-terminal fragments of endogenous tachykinins are pharmacophores responsible for interaction with the tachykinin receptors NK1, NK2 and NK3. The N-terminal fragments are responsible for modulation of receptor selectivity and interactions with other receptor systems. To evaluate and separate the function of an NK-pharmacophore from the activity of its parent neurokinin, KFFGLM-NH2 was synthesized in both tritiated and unlabeled forms. It has been proposed that the obtained NK-binding profiles of specific reference ligands and KFFGLM-NH2 differentiate monomeric and dimeric forms of NK receptors. We hypothesize that dimers of NK receptors could be specific receptor(s) for C-terminal fragments of all neurokinins as well as their C-terminal fragments, including H-KFFGLM-NH2. Dissociation of dimers into monomers opens access to additional allosteric binding sites. Fully elongated undecapeptide substance P interacts with both the "tachykinin pocket" and the "allosteric pocket" on the monomeric NK1 receptor, resulting in high and selective activation. However, C-terminal hexapeptide fragment analogues, recognizing only the "tachykinin pocket", may have less specific interactions with all tachykinin receptors in both monomeric and dimeric forms.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tomczyszyn
authors.forename: Balazs
authors.initials: B
authors.lastname: Csibrany
authors.forename: Attila
authors.initials: A
authors.lastname: Keresztes
authors.forename: Jayapal Reddy
authors.initials: JR
authors.lastname: Mallareddy
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dyniewicz
authors.affiliation: Aleksandra Misicka, Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland, e-mail: misicka@chem.uw.edu.pl.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Misicka
authors.forename: Geza
authors.initials: G
authors.lastname: Toth
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D005260:Female; D008297:Male; D015288:Neurokinin A / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D015320:Tachykinins / Q000378:metabolism*
chemical_list: D010455:Peptides; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D013373:Substance P; D015288:Neurokinin A