Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

Abstract

G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

“…Topological analysis of multiple GPCR structures using computational algorithms revealed a high diversity of the allosteric binding sites as the ligands could locate within the ECLs, between TM helices and within the ICLs (see Figure 4 and [23]). Similarly to other GPCRs [24,25], allosteric modulation of rhodopsin also was suggested [26][27][28][29].…”

“…(see Figure 4 and [23]). Similarly to other GPCRs [24,25], allosteric modulation of rhodopsin also was suggested [26][27][28][29]. Structural analysis of dark state rhodopsin, its photoactivated Meta II state and opsin suggested that the allosteric sites emerge only after light-induced rearrangement of TM helices within the Meta II and opsin structures and involve either rhodopsin's ICLs or ECLs.…”

“…Interestingly, natural products-derived polyphenolic compounds such as anthocyanin and flavonoids were identified as rhodopsin's allosteric modulators that change the rates of rhodopsin regeneration or Gt binding and signaling activation. As suggested, anthocyanins accommodate the cytoplasmic allosteric binding site in rod opsin [28,29], while flavonoids bind rather to the extracellular region of this receptor [17,24]. As noted, flavonoids also improve stability, folding and membrane targeting of RP-linked specific rod opsin mutants [20].…”

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

“…The advantages that these compounds could bring to the clinic have fostered their search, with four of them eventually being approved for clinical use: the positive allosteric modulator of the calcium-sensing receptor cinacalcet used for primary and secondary hyperparathyroidism and severe hypercalcemia; the allosteric antagonist of purinergic P2Y 12 receptor ticagrelor as an anti-thrombotic; the negative allosteric modulator maraviroc for the C-C chemokine CCR 5 receptor; and plerixafor for the C-X-C chemokine CXCR 4 receptor, used for HIV infection and bone marrow transplantation. Many other molecules are currently in clinical trial [ 115 ]. This tremendous progress was made possible by GPCR crystal structures, a variety of functional assays, and in silico computer-based modeling that have improved and optimized the design and development of these drugs.…”

Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

“…G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that detect and transmit a large array of extracellular signals (i.e., sensory stimuli, hormones, neurotransmitters), which allow regulating many different physiological functions (i.e., vision, blood pressure, central nervous system activity) [1]. Accordingly, these kinds of receptors represent the main target (~35%) of clinically used drugs [2]. Most GPCR-targeting drugs consist of ligands, either agonists or antagonists, which bind to the endogenous ligand (orthosteric) binding site.…”