eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
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SCImago Journal & Country Rank
4/2014
vol. 52
 
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abstract:

Original article
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?

Aleksandra Tomczyszyn
,
Balazs Csibrany
,
Attila Keresztes
,
Jayapal Reddy Mallareddy
,
Jolanta Dyniewicz
,
Aleksandra Misicka
,
Geza Toth
,
Andrzej W. Lipkowski

Folia Neuropathol 2014; 52 (4): 383-393
Online publish date: 2014/12/30
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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.
keywords:

neurokinin (tachykinin), receptor binding, radioligand, GPCR monomer, dimer, allosteric modulation

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