High-Affinity Neuropeptide Y Receptor Antagonists

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-09, Vol.92 (20), p.9067-9071
• Main Authors: Daniels, Alejandro J., Matthews, Jessica E., Slepetis, Ruta J., Jansen, Marilyn, Viveros, O. Humberto, Tadepalli, Anjaneyulu, Harrington, Wallace, Heyer, Dennis, Landavazo, Antonio, Leban, Johann J., Spaltenstein, Andrew
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Boluses; Brain - metabolism; Calcium; Calcium - metabolism; Cell Line; Dosage; Humans; Inhibitory concentration 50; Kidney - metabolism; Kidneys; Kinetics; Leukemia, Erythroblastic, Acute; Male; Mammals; Molecular Sequence Data; Neuroblastoma; Neurology; Neurons; Neuropeptide Y - metabolism; Neuropeptide Y - pharmacology; Neuropeptides; Organ Specificity; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Perfusion; Pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - metabolism; Structure-Activity Relationship; Swine; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.20.9067

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukmia cell intracellular calcium mobilization, perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.