Structure−Activity Studies Including a Ψ(CH2-NH) Scan of Peptide YY (PYY) Active Site, PYY(22−36), for Interaction with Rat Intestinal PYY Receptors: Development of Analogues with Potent in Vivo Activity in the Intestine
| ISSN: | 1520-4804 0022-2623 |
|---|---|
| DOI: | 10.1021/jm000052z |
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2f16b6df23d6ce9f8e0ff5228a8b342d https://doi.org/10.1021/jm000052z |
| Přírůstkové číslo: | edsair.doi.dedup.....2f16b6df23d6ce9f8e0ff5228a8b342d |
| Autor: | Zhiyong Tao, Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Claude Roze, William T. Chance, David W. McFadden, Marc Laburthe, Carson D. Liu, John E. Taylor, Thierry Voisin, Josef E. Fischer, Weixu Zhai, Peter E. Eden, Meiczyslawa Stein |
| Rok vydání: | 2000 |
| Předmět: |
medicine.medical_specialty
Colon Peptide hormone Intestinal absorption Cell Line Structure-Activity Relationship chemistry.chemical_compound Dogs Ileum In vivo Internal medicine Drug Discovery medicine Peptide synthesis Animals Peptide YY Intestinal Mucosa Receptor Chemistry digestive oral and skin physiology Neuropeptide Y receptor Peptide Fragments Rats Receptors Neuropeptide Y Intestines Jejunum Endocrinology Intestinal Absorption Gastrointestinal hormone Molecular Medicine hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 43:3420-3427 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm000052z |
| Popis: | Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions. |
| Databáze: | OpenAIRE |
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