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Identification of novel selective V-2 receptor non-peptide agonists
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2008 (English)In: Biochemical Pharmacology, ISSN 0006-2952, Vol. 76, no 9, 1134-1141 p.Article in journal (Refereed) Published
Abstract [en]

Peptides with agonist activity at the vasopressin V-2 receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V-1b receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V-2 receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT (R)), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V-2 receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V-2 receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V-2 receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V-2 receptor agonist deficiency.

Place, publisher, year, edition, pages
2008. Vol. 76, no 9, 1134-1141 p.
Keyword [en]
Vasopressin, V-2 receptor, Diabetes insipidus, Partial agonist, HTS
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-107826DOI: 10.1016/j.bcp.2008.08.004ISI: 000260568900007OAI: oai:DiVA.org:uu-107826DiVA: diva2:233275
Available from: 2009-08-31 Created: 2009-08-31 Last updated: 2009-08-31Bibliographically approved

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