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Other non-peptidic UT antagonists based on the quinoline template include the 2-aminoalkyl quinolin-4-ones 22 (51, 52) disclosed in two patent applications that were published in 2002. A range of substituents in the quinolone benzo ring as well as the 2-position are claimed in these applications and the biological activity at the hUT reported is in the low nanomolar to micromolar range. Structurally related to the quinolin-4-ones, the corresponding quinoiine diamines 23 (hUT K, = 90 nM) have also been investigated for UT antagonism (53). Furthermore, the similarity in some of the quinoiine 2-substituents claimed in these applications indicate that the two series are indeed related and suggests that perhaps they bind to the receptor in a similar manner.

22 23

Further evidence that the bicyclic quinoiine nucleus appears to provide a particularly permissive template for UT antagonism is provided by yet another patent application from a Swiss group claiming 1,2,3,4-tetrahydroisoquinolinyl and analogs, primarily as antihypertensives (54). Using a rhabdomyosarcoma cell line known to express hUT endogenously (54), the binding affinity of compounds in this class in a radiolabeled competition binding assay ([125l]-hU-ll) was determined to be in the 67 -550 nM range. Moreover, some of the compounds (e.g. 24) were effective in blocking the U-ll induced contractions of an isolated rat aortic arch indicating that they possess at least some binding affinity for the rat UT ortholog. However, the nature of the antagonism (competitive or insurmountable) in the tissue based assay

Compound

Ar

hUT Binding K¡

Rat aortic arch contraction pD2'

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