Ureas binding affinities

A limited series of amide replacements have been examined including thioamides (219) [163], reverse amides (220) [164], heterocycles (221) [164], ethers (222) [165], carbamates (223), (224) [165], ureas (225) [165] and ketones (226) [166] (see Table 6.19). In general, replacement of the amide results in a loss of binding affinity compared to AEA. In some cases, replacement of the amide results in increased stability with regard to hydrolysis by FAAH [164, 165]. 

Recently, Kelly and Kim have compared the relative binding affinities of urea and bisurea 33 and 34 with carboxylate and its isosteres. They find that both hosts preferentially associate with functionalities according to the following ranking ArOPO - > ArPO - > ArCOj > ArP(OH)02 > Ar0P(0H)02 > ArSOj > ArSOj 5-lactone > ArNOj. 

Imidazolyljpiperidine containing urea, guanidine, amidine, and carbamate analogs have been mentioned in the patent literature, but very little information other than their receptor binding affinities is available [2,3,11,13]. The tritium labeled S-... 

What are the criteria for regarding a compound as a TS analog The observation that the binding affinity of an inhibitor is greater than that of a substrate, i.e., X, < XM, is insufficient as many potent inhibitors bind differently to an enzyme than the substrate examples are methotraxate, inhibiting dihydrofolate reductase (DHFR) X] = 0.15 pM (Werkheiser, 1961), and sulfonyl urea herbicides, inhibiting acetolactate synthase (ALS) at picomolar levels. 

Tongraung, Chantarasiri, and Tuntulani have reported two calix[4]arenes 15 and 16, one with urea appendages and a second with a crown strap in addition to the urea arms. These systems were found to bind tetrabutylammonium dihydrogen phosphate with a K, > 200 M 1 in DMSO-d6. In line with the authors expectations, the anion-binding affinities were then found to be enhanced upon the addition of sodium cation. For instance, in the presence of this cation, the association constant for calix[4]arene 16 increased to Ka = 1030 M-1 (as the PF6 salt DMSO-d6 solution) [55]. 

Kelly and Kim have carried out a detailed study of the relative binding affinities of carboxylate, nitro, phosphate, phosphonate, sulfonate and 5-lactones with a urea-derived host (Figure 105) [138]. The effects of solvents on the binding affinity were also studied. This bis(urea) receptor was found to bind isophthalate in DMSO-dg with a greater than 10 M- . 

FIGURE 15.37 Binding affinities for various urea bioisosteres acting as antagonists at the NPY Y] receptor. 

Replacement of the amido group by a carbamate group decreases affinity for CBl. However, when the amido group is replaced by substituted ureas (60, Fig. 16) binding affinity as well as stability towards amidase hydrolysis is increased compared to anandamide (Ng et al. 1999). 

This approach has been used primarily to study photosynthesis, for example to introduce tolerance to a variety of stress conditions. Many studies have been successful in verifying the effea of single amino acid modifications on herbicide binding affinity. High affinity binding to the D1 protein is a useful property for the detection of herbicides. A fluorescence biosensor based on mutants resistant to various herbicide subclasses was developed, it makes possible to distinguish between subclasses of herbicides (e.g., triazines from urea and phenolic type herbicides). ... 

Table 9.2 Binding affinity of N-octy -N - p-tolyt)urea...

Table 9.3 Binding affinity of urea derivatives with acetate ...

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