ABSTRACT
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.
Subject(s)
Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/metabolism , Receptors, Vasopressin/agonists , Receptors, Vasopressin/metabolism , 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 , Rats , Rats, Brattleboro , Vasopressins/deficiency , Vasopressins/genetics , Vasopressins/metabolism , Vasopressins/therapeutic useABSTRACT
Because of the limitations and liabilities of current testosterone therapies, non-steroidal tissue-selective androgen receptor modulators may provide a clinically meaningful advance in therapy. Using a functional cell-based assay AC-262536 was identified as a potent and selective AR ligand, with partial agonist activity relative to the natural androgen testosterone. A 2-week chronic study in castrated male rats indicated that AC-262536 significantly improves anabolic parameters in these animals, especially in stimulating the growth of the levator ani and in suppressing elevated LH levels. In sharp contrast to testosterone, AC-262536 has weak androgenic effects, as measured by prostate and seminal vesicle weights. Thus, AC-262536 represents a novel class of selective androgen receptor modulators (SARMs) with beneficial anabolic effects.
