Vasopressin Via antagonists

Further, a novel series of vasopressin Via antagonists has been synthesized, and subnanomolar affinities at the human Via receptor have been achieved. On oral dosing, two members of the series, structures I and II of Fig. 41, reached brain levels 100 times their in vitro receptor affinities. These molecules have been further developed for human clinical evaluation [381]. 

Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G. Nonpeptide vasopressin receptor antagonists development of selective and orally active Via, V2 and Vlb receptor ligands. Prog Brain Res 2002 139 197-210. 

Non-peptide vasopressin receptor antagonists include relcovaptan (an antagonist at Vla receptors), lixivaptan, satavaptan, and tolvaptan (V2), and conivaptan (mixed Via/v2)- They have been used in the treatment of hyponatremia. 

In CHO cells transfected with human V], and V2 vasopressin receptors, 1 inhibits [3H]-AVP binding with K/s of 4.3 and 1.9 nM, respectively.15 Compound 1 demonstrates similar activity on rat Vla and V2 receptors, with Kj s of 0.48 nM and 3.0 nM (Table 1). As a result of significant structural homology between the vasopressin and the oxytocin receptors, 1 and AVP also demonstrate significant oxytocin receptor affinities (rat receptor Kt s of 44.4 nM and 3.4 nM, respectively).16 As seen in Table 1, the balanced binding affinities of 1 toward rat Via and V2 receptors closely parallel those of AVP in contrast, vasopressin receptor antagonists mozavaptan hydrochloride (2) and tolvaptan (3) demonstrate moderate to significant V2 receptor selectivity. 

Antagonists of the vasoconstrictor action of vasopressin are also available. The peptide antagonist (l-[B-mercapto-B,B-cyclopentamethylenepropionic acid]-2-[0 -methyl]tyrosine) arginine vasopressin also has antioxytocic activity but does not antagonize the antidiuretic action of vasopressin. Recently, nonpeptide, orally active Via receptor antagonists have been discovered, an example being relcovaptan. 

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