Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders

Abstract

G protein-coupled receptors (GPCRs) are one of the most important classes of proteins in the genome, not only because of their tremendous molecular diversity but because they are the targets of nearly 50% of current pharmacotherapeutics. The majority of these drugs affect GPCR activity by binding to a similar molecular site as the endogenous cognate ligand for the receptor. These "orthosterically" targeted drugs currently dominate the existing pharmacopeia. Over the past two decades, novel opportunities for drug discovery have risen from a greater understanding of the complexity of GPCR signaling. A striking example of this is the appreciation that many GPCRs possess functional allosteric binding sites. Allosteric modulator ligands bind receptor domains topographically distinct from the orthosteric site, altering the biological activity of the orthosteric ligand by changing its binding affinity, functional efficacy, or both. This additional receptor signaling complexity can be embraced and exploited for the next generation of GPCR-targeted therapies. Despite the challenges associated with detecting and quantifying the myriad of possible allosteric effects on GPCR activity, allosteric ligands offer the prospect of engendering a facile stimulus-bias in orthosteric ligand signaling, paving the way for not only receptor-selective but also signaling pathway-selective therapies. Allosteric modulators possess specific advantages when considering the treatment of multifactorial syndromes, such as metabolic diseases or age-related cognitive impairment, because they may not greatly affect neurotransmitter or hormone release patterns, thus maintaining the integrity of complex signaling networks that underlie perception, memory patterns, or neuroendocrinological axes while introducing therapeutically beneficial signal bias.Heptahelical GPCRs are ubiquitously expressed throughout eukaryotic organisms and can account for as much as 3 to 4% of the genome (Foord, 2002). By detecting ligands in the extracellular milieu, they transmit environmental information from outside a cell to the interior. At the same time, changes in the expression of GPCRs or receptor-associated regulatory proteins under varying physiological conditions

Regulation ofβ2-Adrenergic Receptor Function by Conformationally Selective Single-Domain Intrabodies

“…Although most studies have focused on using orthosteric ligands, the use of allosteric modulators to further fine-tune receptor function has become of recent interest (Conn et al, 2009;Wang et al, 2009;Wang and Lewis, 2013). Herein, we explored the ability of a panel of closely related single-domain Camelid heavy-chain antibodies (nanobodies) to allosterically target and stabilize distinct agonist-bound ("active") and antagonist-bound ("inactive") b 2 AR conformations.…”

Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists

“…How Smo is regulated and whether Smo is modulated by an endogenous ligand remains unknown. However, allosteric ligands acting at the level of the heptahelical domain of GPCRs have been characterized recently and represent a novel therapeutic strategy (Conn et al, 2009;Wang et al, 2009a). MRT-10 and MRT-14 block Bodipy-cyclopamine binding to mouse Smo, suggesting that both molecules are acting at the same site or at allosteric sites.…”

GABAB Receptor-Positive Modulators: Enhancement of GABAB Receptor Agonist Effects In Vivo

“…Allosteric modulators alter the activity of the endogenous ligand by binding to receptor sites that are different from the orthosteric site where the endogenous ligand acts (Christopoulos, 2002;Pin and Prézeau, 2007;Conn et al, 2009;Wang et al, 2009). There is currently much interest in allosteric modulators, because by discriminating between activated and nonactivated receptors, they may have a broader therapeutic window than ligands that indiscriminatingly alter the activity of all receptors.…”