Pharmacological characterization of RWJ-676070, a dual vasopressin V1A/V2 receptor antagonist
| Autor: | Keith T. Demarest, Wai-man Cheung, Philip J. Rybczynski, Lisa Minor, Bruce P. Damiano, Pamela G. Wines, Tom Jay Parry, Min Xiang, Lawrence de Garavilla, Patricia Andrade-Gordon, Bruce E. Maryanoff, Joseph W. Gunnet |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Vasopressin Platelet Aggregation Arginine Vasopressins medicine.drug_class Neuropeptide Blood Pressure In Vitro Techniques Dogs Heart Rate Rats Inbred SHR Internal medicine Arginine vasopressin receptor 2 medicine Animals Humans Spiro Compounds Receptor Pharmacology Dose-Response Relationship Drug business.industry Antagonist Benzazepines Rats Macaca fascicularis Endocrinology Vasoconstriction Hypertension Female medicine.symptom business Antidiuretic Hormone Receptor Antagonists Vasopressin Antagonists |
| Zdroj: | European Journal of Pharmacology. 590:333-342 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2008.06.010 |
| Popis: | The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V 1A and V 2 receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V 1A and V 2 receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V 1A , V 1B or V 2 receptors. Its inhibition of V 1A receptor-mediated contraction of vascular rings and platelet aggregation was determined. V 2 receptor-medated aquaresis was determined in rats, dogs and monkeys. V 1A receptor-mediated inhibitory activity was assessed in vivo in a vasopressin-induced hypertension model and in normotensive rats and in two hypertensive rat models. RWJ-676070 inhibited AVP binding to human V 1A and V 2 receptors (Ki = 1 and 14 nM, respectively). RWJ-676070 inhibited V 1A receptor-induced intracellular calcium mobilization and V 2 receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V 1A receptors. RWJ-676070 inhibited V 1A receptor-mediated vasoconstriction in rat and dog vascular rings and AVP-induced human platelet aggregation. Dose dependent aquaresis was demonstrated in rats, dogs and monkeys following oral administration. RWJ-676070 inhibited AVP-induced hypertension in rats but had no effect on arterial pressure in normotensive and spontaneously hypertensive rats but did decrease arterial pressure in Dahl, salt-sensitive hypertensive rats. RWJ-676070 is a new, potent antagonist of V 1A and V 2 receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V 1A and V 2 receptors. |
| Databáze: | OpenAIRE |
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