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Opportunities and Challenges in the Discovery of Allosteric Modulators of Gpcrs for Treating CNS Disorders

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Opportunities and Challenges in the Discovery of Allosteric Modulators of Gpcrs for Treating CNS Disorders REVIEWS Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders P. Jeffrey Conn1, Craig W. Lindsley1, Jens Meiler2 and Colleen M. Niswender1 Abstract | Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system. The G protein-coupled receptors (GPCRs), which are (CNS). In addition, some GPCRs are activated by enzymatic also known as seven-transmembrane receptors (7TMRs), cleavage. Alternative strategies for modulation may are crucial for transducing signals from the extracellular provide advantages in the development of thera­peutic environment into intracellular changes in cell function. agents that target some receptors. Furthermore, as GPCRs are activated by a diverse range of ligands and orthosteric binding sites are often highly conserved, it is stimuli, including hormones, neurotransmitters, mem- difficult to achieve high selectivity for individual GPCR brane lipids, ions, odorants, enzymes and photons of light, subtypes. The need to develop new approaches for tar- and have diverse roles in every cell and organ system. geting GPCRs is especially urgent for neurological and Human GPCRs are subdivided into four major classes (A, psychiatric diseases, which have been especially challeng- B, C and F) on the basis of their primary sequence homol- ing to address therapeutically and have historically had a ogy1,2. Given the roles of GPCRs in cellular responses to very high attrition rate4. extracellular ligands, it is not surprising that these recep- tors have been among the most successful of drug targets3. Allosteric modulators of GPCRs Despite the proven success of GPCRs as drug targets, Interestingly, CNS drug discovery efforts to target ligand- many intense efforts to develop selective ligands or gated ion channel neurotransmitter receptors have drug candidates for GPCRs have failed. Thus, there is a focused primarily on developing ligands that interact with major need to develop new approaches for the discovery allosteric sites that are topographically distinct from the of therapeutic agents that target this important class of orthosteric neurotransmitter site5,6. By binding to allos- receptors. Traditionally, drugs that target GPCRs bind teric sites, such ligands can act as either positive allosteric 1Department of Pharmacology, to the same site as the endogenous agonist (referred to modulators (PAMs) or negative allosteric modulators Vanderbilt Center for as the orthosteric site), to either activate or inhibit the (NAMs) to potentiate or inhibit activation of the receptor Neuroscience Drug Discovery, receptor. Although this is a strategy well suited for some by the endogenous agonist, respectively. Selective PAMs Vanderbilt University Medical Center, Nashville, receptors, many GPCRs respond to stimuli such as of GABAA (γ‑aminobutyric acid type A) receptors, such Tennessee 1215D LH, USA. light, protons, divalent cations, highly charged nucleo- as benzodiazepines and barbiturates, were among the 2Department of Chemistry, tides, peptides and proteins; in many of these cases, these earliest-approved drugs for the treatment of CNS dis- Vanderbilt University, Nashville, endogenous ligands cannot be easily modified to retain orders7. These allosteric modulators can provide many Tennessee 37232, USA. drug-like properties. For example, many amino acids potential advantages over traditional agonists, including Correspondence to P.J.C. e-mail: and peptides cannot cross the blood–brain barrier, the requirement for the synaptic release of the neuro­ [email protected] meaning that alternative ligands must be developed to transmitter and the activation of the receptor by the doi:10.1038/nrd4308 modulate certain targets in the central nervous system endogenous agonist. However, optimization of allosteric 692 | SEPTEMBER 2014 | VOLUME 13 www.nature.com/reviews/drugdisc © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS modulators for GPCRs did not become practicable until sites and block their actions19–21. Although they are not the late 1990s and early 2000s, when the advent of high- pursued as drug candidates themselves, NALs provide throughput functional screening technologies enabled important tools to validate binding sites and could theo- the study of the functional effects of small molecules on retically serve as candidates for radiolabelling or PET- GPCR signalling that were independent of the effects (positron emission tomography)‑ligand development if on orthosteric ligand binding. Over the past decade, the they possess sufficiently high affinity. discovery and understanding of allosteric modulators The diverse effects of allosteric ligands on receptor have gained tremendous momentum, and GPCR allos- behaviour have been outlined in detail in multiple excel- teric modulators are now marketed as therapeutic agents lent reviews and can be described and quantified by for the treatment of hyperparathyroidism8,9 and HIV equations that are based on various ternary-complex infections10. mass-action models. These equations take the inter­actions To date, no GPCR allosteric modulators have been among the receptor, orthosteric ligands, allosteric ligands approved for the treatment of psychiatric and neurological and effector proteins into account and provide a compu- disorders. However, multiple allosteric modulators have tational approach to define the magnitude and direction entered clinical development (TABLE 1). Phase II clinical of an allosteric effect, using one or more cooperativity trials have now demonstrated promising effects of metabo- factors18,22. More recently, an operational model of allos- tropic glutamate receptor 5 (mGluR5) NAMs in anxiety terism that describes the allosteric modulation of both and affective disorders, Parkinson’s disease and fragile X affinity and efficacy was introduced; this model also syndrome11,12. More recently, a novel mGluR2 PAM incorporates the ability of a compound to induce allosteric entered Phase II testing for schizophrenia and anxious agonism23–25. Briefly, in the operational model, modula- depression13,14, and Merck has announced the initiation of tion of binding affinity is governed by a cooperativity a Phase II trial of a PAM that targets the M1­ receptor — a factor, which is denoted as α, and allosteric modulation of subtype of muscarinic acetylcholine receptors (mAChRs) efficacy is incorporated by the introduction of the para­ — in patients with Alzheimer’s disease (ClinicalTrials.gov meter β. In addition, a composite cooperativity parameter identifier: NCT01852110). Other allosteric modulators are (known as logαβ) can be used to incorporate the modula- now in late discovery or preclinical development, includ- tion of both affinity and efficacy. As some PAMs also have ing mGluR5 PAMs for schizophrenia15; mGluR4 PAMs intrinsic efficacy in the absence of an orthosteric agonist, 16 for Parkinson’s disease ; and M4‑receptor PAMs for the the parameters τΑ and τB have also been incorporated to treatment of psychosis associated with schizophrenia and account for the intrinsic efficacy of the orthosteric and psychosis associated with Alzheimer’s disease17 (TABLE 1). allosteric ligands, respectively. Results from early optimization and animal studies are This operational model of allosterism has been highly now emerging for allosteric modulators of a range of other useful in quantifying different aspects of allosteric modula- CNS GPCRs from families A (Supplementary informa- tor function and can provide valuable information about tion S1 (table)), B (Supplementary information S2 (table)) cooperativity factors and the structure–activity relation- and C (Supplementary information S3 (table)) and are ships (SARs) of predicted affinities when conducting indicative of a healthy pipeline of novel allosteric mod- a lead-optimization programme. To test the validity of ulators that hold promise for the treatment of multiple the model, Gregory et al.26 recently took advantage of the neurological and psychiatric disorders. radioligands and the range of allosteric modulators for mGluR5. The study confirmed that for mGluR5 PAMs Allosteric modulator pharmacology and NAMs, with diverse chemical scaffolds and vary- PAMs, NAMs and NALs. GPCRs are dynamic proteins ing degrees of cooperativity, affinity estimates that were that spontaneously transition between multiple func- derived from functional assays that used the operational tionally distinct conformational states18,19. These include model fitted well with affinities that were measured in states with varying affinities for orthosteric ligands, as radioligand-binding experiments. It should be noted, how- well as different interactions with G proteins and other ever, that the functional estimates of affinity may change effector or signalling molecules. PAMs and NAMs are depending
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