Allosteric Modulation of Purine and Pyrimidine Receptors

Abstract

Among the purine and pyrimidine receptors, the discovery of small molecular allosteric modulators has been most highly advanced for the A1 and A3 ARs. These AR modulators have allosteric effects that are structurally separated from the orthosteric effects in SAR studies. The benzoylthiophene derivatives tend to act as allosteric agonists, as well as selective positive allosteric modulators (PAMs) of the A1 AR. A 2-amino-3-aroylthiophene derivative T-62 has been under development as a PAM of the A1 AR for the treatment of chronic pain. Several structurally distinct classes of allosteric modulators of the human A3 AR have been reported: 3-(2-pyridinyl)isoquinolines, 2,4-disubstituted quinolines, 1H-imidazo-[4,5-c]quinolin-4-amines, endocannabinoid 2-arachidonylglycerol and the food dye Brilliant Black BN. Site-directed mutagenesis of A1 and A3 ARs has identified residues associated with the allosteric effect, distinct from those that affect orthosteric binding. A few small molecular allosteric modulators have been reported for several of the P2X ligand-gated ion channels and the G protein-coupled P2Y receptor nucleotides. Metal ion modulation of the P2X receptors has been extensively explored. The allosteric approach to modulation of purine and pyrimidine receptors looks promising for development of drugs that are event-specific and site-specific in action.

Health safety issues of synthetic food colorants

“…This could be a promising direction for new drug development (Jacobson et al, 2011;May et al, 2010), hence suggesting that Brilliant Black has certain pharmacological activity at higher doses.…”

Species differences and mechanism of action of A3 adenosine receptor allosteric modulators

“…This study provides evidence that allosteric pharmacology of the A 3 AR displays prominent species variability. This information is important for future development of this class of compounds for therapeutic use [8,20] and should be considered when validating A 3 AR modulation by PAMs in animal models. It will be useful to focus efforts in future investigations to develop pan-species A 3 AR PAMs with minimal negative allosteric properties.…”

“…Allosteric modulators of G protein-coupled receptors (GPCRs) are ligands that alter the affinity or intrinsic activity of orthosteric ligands by interacting with a distinctly different binding site on the receptor [7][8][9][10]. From a therapeutic perspective, allosteric modulators have the advantage of regulating activity of an endogenous ligand in a spatially and temporally specific manner [7][8][9][10]. Allosteric ligands typically mediate their effects by inducing conformational changes in the receptor that alter orthosteric agonist binding affinity and/or intrinsic activity thereby causing positive or negative allosteric modulation.…”

Allosteric regulation of the P2X4 receptor channel pore dilation

“…The family of P2X receptors (P2XR) belongs to the superfamily of ligand-gated ion channels orthosterically activated by extracellular adenosine triphosphate (ATP) [17] and modulated by numerous allosteric ligands [9, 4]. These receptors are homo- or heterotrimeric proteins, with three intersubunit ATP binding sites located extracellularly, whereas allosteric binding sites are located within all segments of P2XR protein molecule.…”