Allosteric Enhancers of A₁Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding

Abstract

Endogenous ligands of G protein-coupled receptors bind to orthosteric sites that are topologically distinct from allosteric sites. Certain aminothiophenes such as (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]-methanone (PD81,723) and 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-biphenyl-4-yl-methanone (ATL525) are positive allosteric regulators, or enhancers, of the human A 1 adenosine receptor (A 1 AR). In equilibrium binding assays, 125

Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators

“…The first is that these compounds can behave as agonists of the receptor in their own right, as evidenced by whole-cell assays of ERK1/2 phosphorylation and cAMP accumulation; the lack of effect on calcium mobilization most likely reflects the poor coupling of this latter pathway to A 1 receptor activation. The finding of direct allosteric agonism with 2A3BTs has been noted previously Bhattacharya and Linden, 1995;Musser et al, 1999;Baraldi et al, 2000;Figler et al, 2003;Aurelio et al, 2009), suggesting that their mechanism of allosteric potentiation is likely to involve, at least in part, an increase in the proportion of receptors in an active state and, hence, an increase in receptor-G protein coupling Bhattacharya and Linden, 1995;Hall, 2000). However, a key novel finding in our current study was the reversal in potency orders of the 2A3BTs and R-PIA for signaling to ERK1/2 relative to cAMP inhibition (Fig.…”

“…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.…”

Redetermination of the structure of N-(2-benzoyl-4-chlorophenyl)-2- chloroacetamide, C15H11Cl2NO2

“…4-Aminobenzophenones have high anti-inflammatory activity [2], a benzophenyl cyano derivative acts as a vasorelaxant [3] and the piperidinyl derivative produces analgesia [4]. Certain aminothiophenes of phenylmethanone are positive allosteric regulators of the human A1 adenosine receptor [5] and biphenyl derivatives show moderate to high activity against Mycobacterium tuberculosis in in vitro studies [6]. Recently a related compound has been reported by our research group [7].The structure of the title compound -that has been reported at room temperature only so far [8] -was re-determined at 200 K to allow for the comparison of metrical parameters with other members of the series to be investigated.…”

“…The latter contacts connect the molecules to centrosymmetric dimers. In terms of graph-set analysis [5,6], the unary level descriptors for these contacts are S(6) and R 2 2 . In addition, a C-H···p interaction is observed that is supported by one of the hydrogen atoms of the methylene group and the aromatic system of the unsubstituted phenyl group.…”

Adenosine Receptors and Angiogenesis

“…Small molecule allosteric enhancers of the A 1 receptor, which do not directly activate the receptor but instead enhance the actions of endogenous adenosine by increasing coupling efficiency to G proteins, may prove to be more useful. 22,23 These agents could theoretically lead to angiogenesis in those tissue areas where hypoxia is greatest without affecting systemic hemodynamic parameters. Cardiovascular side-effects may also be minimized by using partial A 1 receptor agonists that elicit submaximal responses even when administered at high doses.…”