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Metabotropic receptors are responsible for so-called ‘slow synaptic transmission’ and mediate the effects of hundreds of peptide and non-peptide neurotransmitters and neuromodulators. Over the past decade or so, a revolution in membrane-protein structural determination has clarified the molecular determinants responsible for the actions of these receptors. This Review focuses on the G protein–coupled receptors (GPCRs) that are targets of neuropsychiatric drugs and shows how insights into the structure and function of these important synaptic proteins are accelerating understanding of their actions. Notably, elucidating the structure and function of GPCRs should enhance the structure-guided discovery of novel chemical tools with which to manipulate and understand these synaptic proteins.

Psychedelic drugs including psilocybin, N,Nʹ-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a ‘gold rush’ of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.Psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have emerging therapeutic potential for neuropsychiatric diseases such as depression and anxiety. In this Perspective, McClure-Begley and Roth discuss the promises and pitfalls of psychedelic pharmacology, including complex activity profiles beyond canonical 5-HT2A receptor activation that continue to be elucidated. They consider progress and challenges for clinical studies, as well as prospects for parsing the therapeutic from psychedelic effects of this class of compounds to develop ‘cleaner’ drugs.

An X-ray structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone reveals an extended binding pocket and indicates structural features that could be used to design drugs that specifically target the D2 receptor. Dopamine's unusual binding technique D2 dopamine receptors are the principal targets for antipsychotic drugs for the treatment of schizophrenia, and offer possibilities for treating depression and Parkinson's disease. However, molecular-level understanding of these receptors is limited, and many available drugs cause serious side-effects as a result of activity at other dopamine receptors. Here, Bryan Roth and colleagues report the crystal structure of the D2 receptor in complex with the antipsychotic drug risperidone. This structure shows an unusual binding mode of the drug, distinct from those observed in the related D3 and D4 receptors, whereby a hydrophobic patch formed by a tryptophan residue regulates the entry and exit of the drug. Mutation at this position reduces the drug residence time, which is believed to be related to side-effects of common antipsychotics. This work hints at ways to develop safer antipsychotic drugs that are selective for D2. Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors 1 . The D2 dopamine receptor (DRD2) is the primary target for both typical 2 and atypical 3 , 4 antipsychotic drugs, and for drugs used to treat Parkinson’s disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors 4 , 5 . Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D 4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D 4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D 4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D 4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D 4 dopamine receptor. Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D 4 dopamine receptor with high affinity.

Bitopic ligands that engage two distinct binding sites offer exciting opportunities for finely tuned control of G protein-coupled receptor signaling. A recent study in PLOS Biology employed click chemistry to generate novel nanobody-small molecule conjugates and demonstrated their logic-gated activity at co-expressed receptor pairs with improved signaling profiles.

G-protein-coupled receptors (GPCRs) remain major drug targets, despite our incomplete understanding of how they signal through 16 non-visual G-protein signal transducers (collectively named the transducerome) to exert their actions. To address this gap, we have developed an open-source suite of 14 optimized bioluminescence resonance energy transfer (BRET) Gαβγ biosensors (named TRUPATH) to interrogate the transducerome with single pathway resolution in cells. Generated through exhaustive protein engineering and empirical testing, the TRUPATH suite of Gαβγ biosensors includes the first Gα15 and GαGustducin probes. In head-to-head studies, TRUPATH biosensors outperformed first-generation sensors at multiple GPCRs and in different cell lines. Benchmarking studies with TRUPATH biosensors recapitulated previously documented signaling bias and revealed new coupling preferences for prototypic and understudied GPCRs with potential in vivo relevance. To enable a greater understanding of GPCR molecular pharmacology by the scientific community, we have made TRUPATH biosensors easily accessible as a kit through Addgene. Development of BRET sensors for nearly all major G proteins show that GPCR–G-protein coupling ranges from promiscuous to extremely specific, Switch III is a novel site for G-protein engineering, and optimal donor–acceptor positioning is non-obvious.

Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures 1 – 4 and ultra-large libraries of virtual compounds 5 , 6 . However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries 7 , new approaches to compound screening are needed 8 , 9 . Here we introduce a modular synthon-based approach—V-SYNTHES—to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold–synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant ( K i ) = 0.9 nM) and CB 2 /CB 1 selectivity (50–200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm. V-SYNTHES, a scalable and computationally cost-effective synthon-based approach to compound screening, identified compounds with a high affinity for CB2 and CB1 in a hierarchical structure-based screen of more than 11 billion compounds.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors 1 . Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants 2 , 3 , 4 , 5 – 6 , although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G gust (also known as gustducin) and G i1 . Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G gust and G i1 . Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants. Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.Deschloroclozapine (DCZ) is a broadly useful chemogenetic agonist for studies using nonhuman primates and mice. DCZ rapidly and reversibly activates DREADDs, and its binding can be visualized noninvasively by positron emission tomography.