Binding nonpeptide antagonist

Nonpeptide Antagonists May Bind Rather Differently from the Agonist.103... 

Amplified Luminescence Proximity Homogeneous Assay (AlphaS-creen ) technology have been reported [50,51]. With an HTS methodology in hand and orthogonal assays previously developed [47-49], nonpeptide antagonists of methyl lysine binding should appear from diversity screening approaches in the near future. 

Over the past decade, considerable effort has been expended on the design and synthesis of nonpeptidic antagonists for the three receptors (NKl-3) to which SP, NKA, and NKB bind. These antagonists could have therapeutic use in conditions such as migraine, arthritis, inflammatory diseases such as cystitis, psoriasis, asthma, anxiety, depression, and emesis (vomiting). A variety of NKl-3 receptor antagonists have been designed and synthesized. The majority of these compounds are polyheterocyclics. 

Two distinct subtypes of Ang II receptors, termed AT and AT2, have been identified on the basis of their differential affinity for antagonists, and their sensitivity to sulfhydryl-reducing agents. AT receptors have a high affinity for losartan and a low affinity for PD 123177 (an experimental nonpeptide antagonist), whereas AT2 receptors have a high affinity for PD 123177 and a low affinity for losartan. Ang II and saralasin (see below) bind equally to both subtypes. The relative proportion of the two subtypes varies from tissue to tissue ATi receptors predominate in vascular smooth muscle. 

As a result of an overlay comparison of SK F 108566 with a representative biphenyltetrazole nonpeptidic antagonist (e.g., see 14), SmithKline Beecham scientists suggested that these two series of antagonists may be binding to the All receptor in a different manner. A discussion of alternate possibilities... 

Figure 6.4 Hypothetical correspondence between receptor binding elements of A-II and nonpeptide antagonists, (a) Pharmacophore of (12) proposed by Duncia et al, [41] (b) alternative proposal by Weinstock et at. [43] (c) model suggested for (19) [43].

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