Pyrazinobenzodiazepines as Potent Nonpeptide Vasopressin Receptor Antagonists

Jay   M.   Matthews; Dennis   J.   Hlasta; Patricia      Andrade-Gordon; Keith   T.   Demarest; Eric      Ericson; Joseph   W.   Gunnet; William      Hageman; Richard      Look; John   B.   Moore; Bruce   E.   Maryanoff

Abstract

We have identified a novel series of tricyclic pyrazinobenzodiazepines, represented by general structure 2, as potent vasopressin receptor antagonists. For example, 3 binds with high affinity to human V2 receptors and is very selective relative to V1a receptors. Compound (R)-(+)-3 exhibited pronounced aquaretic activity in rats and dogs on oral administration.

Keywords: g-protein-coupled receptors, smooth muscle contraction, glycogen, corticotropin, oxazinobenzodiazepines, hydrophobicity, secondary amine, crystallization, oxygen systems

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Letters in Drug Design & Discovery

Title: Pyrazinobenzodiazepines as Potent Nonpeptide Vasopressin Receptor Antagonists

Volume: 2 Issue: 3

Author(s): Jay M. Matthews, Dennis J. Hlasta, Patricia Andrade-Gordon, Keith T. Demarest, Eric Ericson, Joseph W. Gunnet, William Hageman, Richard Look, John B. Moore and Bruce E. Maryanoff

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Keywords: g-protein-coupled receptors, smooth muscle contraction, glycogen, corticotropin, oxazinobenzodiazepines, hydrophobicity, secondary amine, crystallization, oxygen systems

Abstract: We have identified a novel series of tricyclic pyrazinobenzodiazepines, represented by general structure 2, as potent vasopressin receptor antagonists. For example, 3 binds with high affinity to human V2 receptors and is very selective relative to V1a receptors. Compound (R)-(+)-3 exhibited pronounced aquaretic activity in rats and dogs on oral administration.

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Matthews M. Jay, Hlasta J. Dennis, Andrade-Gordon Patricia, Demarest T. Keith, Ericson Eric, Gunnet W. Joseph, Hageman William, Look Richard, Moore B. John and Maryanoff E. Bruce, Pyrazinobenzodiazepines as Potent Nonpeptide Vasopressin Receptor Antagonists, Letters in Drug Design & Discovery 2005; 2 (3) . https://dx.doi.org/10.2174/1570180053765183