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Synthesis and characterization of a selective peptide antagonist of neuropeptide Y vascular postsynaptic receptors
Author(s) -
Lew Michael J.,
Murphy Roger,
Angus James A.
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.tb15352.x
Subject(s) - neuropeptide y receptor , medicine , endocrinology , vas deferens , peptide yy , mesenteric arteries , agonist , chemistry , antagonist , receptor , postsynaptic potential , receptor antagonist , ileum , neuropeptide , biology , artery
1 A cyclic dimeric nonapeptide neuropeptide Y (NPY) receptor antagonist, 1229U91, was synthesized by Fmoc chemistry and dimerised in solution. Its effects were assayed in mesenteric arteries from rats and mice, and in rat vas deferens. 2 Mesenteric arteries were cannulated and pressurised to 55 mmHg and the external diameters continuously measured. NPY, PYY, Leu 31 Pro 34 NPY and NPY(13–36) each caused concentration‐related contractions with the order of potency PYY≥Leu 31 Pro 34 NPY = NPY>NPY (13–36), consistent with the Y 1 receptor subtype. 3 1229U91 had no agonist activity in the arteries but caused a concentration‐related rightward shift of NPY (mouse arteries) or Leu 31 Pro 34 NPY (rat) concentration‐response curves. The antagonism was competitive with pATBs of 7.69±0.15 and 7.47±0.13 in the mouse and rat arteries, respectively. 4 Sympathetic nerves in the vas deferens were stimulated with a single electrical field pulse every 20 s and the twitch responses recorded. NPY, PYY, Leu 31 Pro 34 NPY and NPY(13–36) inhibited the twitches with the order of potency PYY>NPY>NPY(13–36)> > Leu 31 Pro 34 NPY, consistent with the Y 2 receptor subtype. 5 1229U91 inhibited the vas deferens twitch with a shallow concentration‐response curve and a time‐course of inhibition distinct from that of NPY. 1229U91 (30 μ m ) did not cause a rightward shift of the NPY concentration‐response curve. 1229U91 is at least 5 orders of magnitude less potent in the vas deferens than in rat brain Y 2 binding assays reported by others, suggesting that the brain and vas deferens Y 2 receptors are different. 6 It is concluded that 1229U91 is a competitive antagonist of NPY Y 1 vascular receptors and has additional properties that inhibit the electrically evoked twitch of the rat vas deferens.