Structure activity studies of mast cell activation and hypotension induced by neuropeptide Y (NPY), centrally truncated and C‐terminal NPY analogues

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 Y2 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 [Glu4,25,33,35]‐NPY(1–4)‐Ahx‐(25–36) and [Asp4,25,33,35]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 Y2 receptors. There was a statistical correlation between the hypotensive effects expressed as ED10 values (μmol kg−1, which induced a blood pressure decrease of 10 mmHg) and the EC25 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 EC25 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.

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