STRUCTURE-ACTIVITY STUDIES OF MAST-CELL ACTIVATION AND HYPOTENSION INDUCED BY NEUROPEPTIDE-Y (NPY), CENTRALLY TRUNCATED AND C-TERMINAL NPY ANALOGS

1 Neuropeptide-induced histamine release is thought to occur via recep tor-independent mechanisms, with net charge and lipophilicity being im portant factors.2 In this study, the histamine releasing ability of ne uropeptide Y (NPY), two C-terminal segments of NPY and 13 centrally tr uncated NPY analogues was examined. These results were compared with t he ability of the peptides to bind to the Y-2 receptor in the rabbit k idney membrane model and with their hypotensive actions in the anaesth etized-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 rel ease was not linked to the ability of the peptides to displace NPY fro m Y-2 receptors. There was a statistical correlation between the hypot ensive effects expressed as ED(10) values (mu mol kg(-1), which induce d a blood pressure decrease of 10 mmHg) and the EC(25) for histamine r elease (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 n et positive charge (r = -0.93, P = 5.7 x 10(-7)), i.e. increasing the net positive charge caused greater histamine release. However, there w as a 12 fold difference in activity amongst the most positively charge d analogues (+ 5). Helicity did not correlate with histamine releasing ability. 6 In the development of NPY-related drugs the avoidance of c ompounds with net positive charge is recommended.