Allosteric enhancers

Some structure-activity relationships of a further developed R4, R5 alkyl/cycloalkyl series (2a-o, Fig. 10, Table 1) were also investigated. This study [69] revealed structural features that favored allosteric enhancing activity, such as benzoyl lipophilic substitution and thiophene 4-alkyl substitution, while other features, such as thiophene 5-bulky substitution, favored antagonistic properties. Upon further analysis, a... 

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Musser B, Mudumbl RV, Liu J, Olson RD, Vestal RE. Adenosine Ai receptor-dependent and -independent effects of the allosteric enhancer PD 81,723. J Pharmacol Exp Ther 1999 288 446 454. 

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Bhattacharya S, Linden J. The allosteric enhancer, PD 81,723, stabilizes human At adenosine receptor coupling to G proteins. Biochim Biophys Acta 1995 1265 15-21. 

Kourounakis A, Visser C, de Groote M, Ijzerman AP. Differential effects of the allosteric enhancer PD81,723 on agonist and antagonist binding and function at the human wild type and a mutant (T277A) adenosine At receptor. Biochem Pharmacol 2000 61 137-144. 

Van der Klein PAM, Kourounakis AP, Ijzerman AP. Allosteric modulation of the adenosine At receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding. J Med Chem 1999 42 3629-3635. 

Kourounakis AP, Van der Klein PAM, Ijzerman AP. Elucidation of structure-activity relationships of 2-amino-3-benzoylthiophenes Study of their allosteric enhancing versus antagonistic activity on adenosine A receptors. Drug Dev Res 2000 49 227-237. 

Amino-3-aroylthieno[2,3-f]pytidines have been synthesized for their potential to serve as allosteric enhancers at the adenosine Aj receptor <2006BML5530>. Thieno[3,2-f]pyridine derivatives have been found to be potent Lck inhibitors that are highly selective within the Src-family of tyrosine kinases <2007BML1167>. Thieno[3,2-f]pyridine urea compounds have been shown to be potent inhibitors of KDR kinase <2007BML1246>. Thieno[2,3-/ ]pyridine-... 

Enhancement of the binding of agonists to the receptor by allosteric enhancers... 

A further possibility to modulate physiological adenosine or agonistic effects could be allosteric enhancement. Allosteric enhancers described so far enhance the binding of several agonists by up to two-fold so they bind more efficiently, and lower concentrations of the agonist are needed (Bruns et al., 1990). Some of the compounds are claimed to have analgesic properties (Baraldi, 1999) or reported to be active in neuropathic pain (Li et al., 2002). 

In addition to the activation of the A3 AR by orthosteric agonists that are competitive with adenosine, allosteric enhancers of the action of adenosine and synthetic agonists at the A3AR have been identified. The allosteric modulation of the A3AR in vivo would depend on the release of endogenous adenosine in response to tissue or organ stress. Thus, it would amplify a natural protective response to a challenge. 

Fig. 6.9 Summary of known SAR of derivatives of VUF5455 as selective allosteric enhancers of the A3AR...

Gao ZG, Kim SG, Soltysiak KA, Melman N, Ijzerman AP, Jacobson KA (2002a) Selective allosteric enhancement of agonist binding and function at human A3 adenosine receptors by a series of imidazoquinoline derivatives. Mol Pharmacol 62(l) 81-89... 

Batrachotoxin at present remains an important, indeed often essential, tool for mechanistic studies of the function of voltage-dependent sodium channels and for the investigation of the role of depolarization and/or influx of sodium ions on physiological functions. Batrachotoxin has been particularly useful in the study of the function of sodium channels, purified and reconstituted into artificial lipid bilayers. A summary and overview of the extensive studies with batrachotoxin appeared in 1986 (5). Since that time more than 100 articles dealing with the activity of batrachotoxin and/ or the radioligand batrachotoxinin A 20a-[ H]benzoate have appeared, and it is beyond the scope of the present review to summarize this extensive recent literature. A few selected developments are as follows allosteric enhancement of the action of batrachotoxins by pyrethroid insecticides... 

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