Identification of novel selective V2 receptor non-peptide agonists

Biochem Pharmacol. 2008 Oct 30;76(9):1134-41. doi: 10.1016/j.bcp.2008.08.004. Epub 2008 Aug 12.


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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antidiuretic Agents / administration & dosage
  • Antidiuretic Agents / chemical synthesis
  • Deamino Arginine Vasopressin / administration & dosage
  • Deamino Arginine Vasopressin / chemistry
  • Deamino Arginine Vasopressin / metabolism
  • Deamino Arginine Vasopressin / therapeutic use
  • Diabetes Insipidus / prevention & control
  • Diabetes Insipidus / urine
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Mice
  • NIH 3T3 Cells
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Pharmaceutical Preparations / administration & dosage
  • Pharmaceutical Preparations / chemical synthesis*
  • Pharmaceutical Preparations / metabolism*
  • Rats
  • Rats, Brattleboro
  • Receptors, Vasopressin / agonists*
  • Receptors, Vasopressin / metabolism*
  • Vasopressins / deficiency
  • Vasopressins / genetics
  • Vasopressins / metabolism
  • Vasopressins / therapeutic use


  • Antidiuretic Agents
  • Peptides
  • Pharmaceutical Preparations
  • Receptors, Vasopressin
  • Vasopressins
  • Deamino Arginine Vasopressin