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Structure activity studies of mast cell activation and hypotension induced by neuropeptide Y (NPY), centrally truncated and C‐terminal NPY analogues
Author(s) -
Cross L.J. Mark,
BeckSickinger Annette G.,
Bienert Michael,
Gaida Wolfram,
Jung Günther,
Krause Eberhard,
Ennis Madeleine
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15194.x
Subject(s) - neuropeptide y receptor , histamine , chemistry , medicine , endocrinology , neuropeptide , receptor , peptide , mast cell , histamine h3 receptor , biology , antagonist , biochemistry , immunology
1 Neuropeptide‐induced histamine release is thought to occur via receptor‐independent mechanisms, with net charge and lipophilicity being important factors. 2 In this study, the histamine releasing ability of neuropeptide Y (NPY), two C‐terminal segments of NPY and 13 centrally truncated NPY analogues was examined. These results were compared with the ability of the peptides to bind to the Y 2 receptor in the rabbit kidney membrane model and with their hypotensive actions in the anaesthetized‐rat model. 3 All analogues tested, with the exception of [Glu 4,25,33,35 ]‐NPY(1–4)‐Ahx‐(25–36) and [Asp 4,25,33,35 ]NPY(1–4)‐Ahx‐(25–36) which were devoid of histamine releasing activity, evoked a dose‐dependent histamine release but there were marked differences between the peptides. The native peptide was the least active. 4 Histamine release was not linked to the ability of the peptides to displace NPY from Y 2 receptors. There was a statistical correlation between the hypotensive effects expressed as ED 10 values (μmol kg −1 , which induced a blood pressure decrease of 10 mmHg) and the EC 25 for histamine release ( r = 0.62, P = 0.04), although histamine release may not be the sole determinant of the alterations in blood pressure. 5 There was a strong negative correlation between EC 25 for histamine release and net positive charge ( r = −0.93, P = 5.7 × 10 −7 ), i.e. increasing the net positive charge caused greater histamine release. However, there was a 12 fold difference in activity amongst the most positively charged analogues (+ 5). Helicity did not correlate with histamine releasing ability. 6 In the development of NPY‐related drugs the avoidance of compounds with net positive charge is recommended.