2-Amino-3-benzoylthiophene Allosteric Enhancers of A₁ Adenosine Agonist Binding:  New 3, 4-, and 5-Modifications

Abstract

2-Amino-3-aroylthiophenes are agonist allosteric enhancers (AE) at the A(1) adenosine receptor (A(1)AR). Here we report the syntheses of three kinds of novel 2-aminothiophenes and assays of their AE activity at the human A(1)AR (hA(1)AR), namely, (1) 2-amino-4,5-diphenylthiophene-3-carboxylates, 3a-h, (2) 2-amino-3-benzoyl-4,5-diphenylthiophenes, 7a-p, and (3) 2-amino-5-bromo-3-benzoyl-4-phenylthiophenes, 10a-h. An in vitro assay employing the A(1)AR agonist [(125)I]ABA and membranes from CHO-K1 cells stably expressing the hA(1)AR measured an index of AE activity, the ability of a candidate AE to stabilize the agonist-A(1)AR-G protein ternary complex, scored as the percentage of ternary complex remaining after 10 min of dissociation initiated by CPX and GTPgammaS. The AE activity score of 2-amino-4,5-dimethyl-3-(3-trifluoromethylbenzoyl)thiophene (PD 81,723), which was 19%, served as a standard for comparison. Two 3-carboxythiophene 3-trifluoromethylbenzyl esters, 3d (49%) and 3f (63%), had substantial AE activity. The 3-(1-naphthoyl) substituent of 7e (52%) also supported AE activity. Compounds in series 3 tended to be more potent, 10a and 10c having scores of 91 and 80%, respectively. The activity of 2-amino-5-bromo-3-ethoxycarbonyl-4-(3-nitrophenyl)thiophene, 10h (26%), is an exception to the rule that a 3-ethoxycarbonyl substituent cannot support AE activity.

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

“…none of them is focused on the direct synthesis of 5-halogen substituted 2-aminothiophenes. Finally, in 2003 Scammells and co-workers 100 have presented the synthetic pathway to 5-bromo substituted 2-aminothiophenes 29. The reaction was successful it the R-substituted 2-bromo-1-phenylethanones 27 were reacted with 3-oxo-3-phenylpropanenitrile 28 and sulfur in the presence of diethylamine as a base in ethanol (Scheme 15).…”

“…Because the structure-based drug design program through substituted 2-aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophene-based structures in medicinal chemistry. 7,[12][13][14]36,37,51,69,100,101,[119][120][121][122][123][124][125][126][127] It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.…”

Crystal and Molecular Structures of Two 2-Aminothiophene Derivatives

“…The synthesis and properties of these compounds were reviewed in 1999 by Sabinis et al [1] and more recently by Puterová et al [2]. In particular, substituted 2-aminothiophenes with alkyl or cycloalkyl substituents in positions 4 and 5 (see Scheme 1), and aroyl group in position 3 are active as allosteric enhancers at the human A 1 adenosine receptor [3][4][5]. According to these results, the 2-amino and 3-keto groups are necessary for the biological action, and the substituents at position 4 can further increase the activity.…”

Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators

“…Within such a scheme, the interaction with agonists presumably reflects a mixed mode of positive cooperativity and competitive inhibition, whereas the interaction with antagonists reflects both negative cooperativity and competition. Accordingly, many structureactivity relationships have been performed to separate the "allosteric component" from the "orthosteric component" of these ligands (van der Klein et al, 1999;Baraldi et al, 2000;Figler et al, 2003;Lü tjens et al, 2003;Nikolakopoulos et al, 2006;Aurelio et al, 2008Aurelio et al, , 2009Ferguson et al, 2008). Although these studies have yielded ligands with increased allosteric potencies, none has successfully moved away from the 2-aminothiophene scaffold or has been able to completely eradicate the apparently orthosteric/ competitive component of their actions.…”