Abstract
Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.
Highlights
Arginine vasopressin (AVP), a neurohypophysial peptide hormone that is secreted mainly from the posterior pituitary gland in response to low blood volume or high serum osmolality exerts its biological action through three major G-protein-coupled receptors, V1a, V1b and V2 [1,2,3]
A few of them have undergone sufficient clinical trials to be on the market, such as the dual V1a/V2 receptor antagonist conivaptan and the selective V2 receptor antagonist tolvaptan approved for the treatment of hyponatremia in the USA
We report the synthesis and biological evaluation of this series of substituted desloratadine designed as potent AVP V2 receptor agonists
Summary
Arginine vasopressin (AVP), a neurohypophysial peptide hormone that is secreted mainly from the posterior pituitary gland in response to low blood volume or high serum osmolality exerts its biological action through three major G-protein-coupled receptors, V1a, V1b and V2 [1,2,3]. A few of them have undergone sufficient clinical trials to be on the market, such as the dual V1a/V2 receptor antagonist conivaptan and the selective V2 receptor antagonist tolvaptan approved for the treatment of hyponatremia in the USA. Another promising selective AVP V2 receptor antagonist, lixivaptan, is still undergoing phase 3 clinical trials at this moment. We reported some amide and sulfamide derivatives of desloratadine, which are potent AVP V2 receptor antagonists [31]. We report the synthesis and biological evaluation of this series of substituted desloratadine designed as potent AVP V2 receptor agonists
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