Advanced

Identification of novel selective V2 receptor non-peptide agonists

Del Tredici, Andria L. ; Vanover, Kim E. ; Knapp, Anne E. ; Bertozzi, Sine M. ; Nash, Norman R. ; Burstein, Ethan S. ; Lameh, Jelveh ; Currier, Erika A. ; Davis, Robert E. and Brann, Mark R. , et al. (2008) In Biochemical Pharmacology 76(9). p.1134-1141
Abstract

Peptides with agonist activity at the vasopressin V2 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 V1b receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V2 receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT®), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist... (More)

Peptides with agonist activity at the vasopressin V2 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 V1b receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V2 receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT®), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V2 receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V2 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 V2 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 V2 receptor agonist deficiency.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
keywords
Diabetes insipidus, HTS, Partial agonist, V receptor, Vasopressin
in
Biochemical Pharmacology
volume
76
issue
9
pages
1134 - 1141
publisher
Elsevier
external identifiers
  • scopus:53649083128
  • pmid:18761325
ISSN
0006-2952
DOI
10.1016/j.bcp.2008.08.004
language
English
LU publication?
no
id
ec38f598-a22d-4d3a-8a68-0d9e5a6f6354
date added to LUP
2019-10-02 10:19:45
date last changed
2020-01-13 02:26:09
@article{ec38f598-a22d-4d3a-8a68-0d9e5a6f6354,
  abstract     = {<p>Peptides with agonist activity at the vasopressin V<sub>2</sub> 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<sub>1b</sub> receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V<sub>2</sub> receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT<sup>®</sup>), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V<sub>2</sub> receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V<sub>2</sub> 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<sub>2</sub> 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<sub>2</sub> receptor agonist deficiency.</p>},
  author       = {Del Tredici, Andria L. and Vanover, Kim E. and Knapp, Anne E. and Bertozzi, Sine M. and Nash, Norman R. and Burstein, Ethan S. and Lameh, Jelveh and Currier, Erika A. and Davis, Robert E. and Brann, Mark R. and Mohell, Nina and Olsson, Roger and Piu, Fabrice},
  issn         = {0006-2952},
  language     = {eng},
  month        = {10},
  number       = {9},
  pages        = {1134--1141},
  publisher    = {Elsevier},
  series       = {Biochemical Pharmacology},
  title        = {Identification of novel selective V2 receptor non-peptide agonists},
  url          = {http://dx.doi.org/10.1016/j.bcp.2008.08.004},
  doi          = {10.1016/j.bcp.2008.08.004},
  volume       = {76},
  year         = {2008},
}