Receptor binding assay activity

AstraZeneca has filed a patent application on novel bis-aryl compounds as CB1/CB2 agonists that lack CNS penetration and thus avoid the unwanted side effects associated with activation of central CBi receptors [210]. Over 100 compounds are specifically claimed e.g. (321). Compounds were tested in receptor binding assays using human CBi and CB2 receptor preparations. Respective K values were in the ranges 50-5,000 and 15-2,800 nM, although no specific data were presented. 

A recent report on a NR2B selective NMDA receptor antagonist (9) supports the findings of Kalvass and Maurer [56], Rapid equilibration between plasma and CNS coupled with the lack of Pgp substrate activity led the authors to assume that plasma-free and brain-free drug concentrations were equivalent. An ex vivo receptor binding assay showed 50% occupancy at a total plasma concentration of 230 nM. Given a rat-free fraction of 15.3%, the authors concluded that 50% brain occupancy occurred at 35 nM unbound brain concentration, which was in reasonable agreement with the measured Ki of 3.4 nM versus the human receptor. 

Because the chemical structure of a molecule encodes its biological properties, structure has long served as the primary variable and determinant for the discovery of new drugs by medicinal chemists. For this reason, systematic structural modification has been the primary tool of choice to isolate and enhance a desired biologic activity. Moreover, with the relatively recent development of in vitro receptor-binding assays, combinatorial methods of chemical synthesis, and computer graphics, the overall approach to structural modification has become increasingly sophisticated. 

Additional assays have surfaced on both ends of the scale of complexity. Single end point assays such as those for a host of receptor binding and activation assays and enzyme activity modulation assays have been developed and applied to alternative developmental toxicity testing. These assays can be carried out in a... 

Biphalin, in standard receptor-binding assays, shows twice the affinity to mu than delta receptors (Table 1). Structure-activity relationships of a series of symmetric biphalin analogues show that replacing phenylalanine residues with -chlorophenylalanine increases the affinity for delta receptors and decreases it for mu receptors, resulting in more potent and more... 

TABLE 1 Activity of Delta-Selective Ligands in Opioid Receptor Binding Assays and Delta GTP-y[35S] Assays... 

Although the analytical control of each pool was impossible due to the large number of individuals, using a tea bag introduced especially for this purpose, a purity check for the reaction was performed on each pool after each step, and this was assumed as a quality control for the whole library. The library was tested in p- and k-opioid receptor binding assays and in a cr-receptor binding assay. Some preliminary activities for one of the pools in... 

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