Identification of novel selective V2 receptor non-peptide agonists.
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.
Del Tredici
Andria L
AL
ACADIA Pharmaceuticals Inc., San Diego, CA 92121, USA. andriadeltredici@yahoo.com
Vanover
Kim E
KE
Knapp
Anne E
AE
Bertozzi
Sine M
SM
Nash
Norman R
NR
Burstein
Ethan S
ES
Lameh
Jelveh
J
Currier
Erika A
EA
Davis
Robert E
RE
Brann
Mark R
MR
Mohell
Nina
N
Olsson
Roger
R
Piu
Fabrice
F