Focus on research: Drugs and valvular heart disease

[No abstract available

Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs

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

How structure informs and transforms chemogenetics

Chemogenetic technologies such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used to remotely control neuronal and non-neuronal signaling. DREADDs exist for most of the canonical G protein-coupled receptor signaling pathways, and provide a synthetic biology platform useful for elucidating the role of neuronal signaling for brain function. Here, a focused review is provided that shows how recent insights obtained from GPCR structural studies inform our understanding of these chemogenetic tools from a structural perspective

Introduction to the Biochemistry of Pain Special Issue

Both acute and chronic pain represent continued unmet medical needs for millions of individuals in the United States and elsewhere. Thus, for instance, the Centers for Disease Control and Prevention estimated that 20.4% of U.S. adults experienced chronic pain in 2016. Both opioid and non-opioid analgesic agents represent the principal pharmacological treatments for both acute and chronic pain, albeit not without both serious immediate and long-term side effects. For opioids, these include death due to accidental overdose and dependence, and the United States is currently experiencing a crisis related to opioid abuse and deaths due to overdose. Because of this, there is an urgent need for safer and more effective medications. Elucidating the biochemistry and structural biology of pain-related molecular targets represents an initial first step toward the discovery and development of safer analgesics

Dr. Roth replies

[No abstract available

Structural insights from G-protein-coupled receptor complexes enable the rational engineering of improved light-activated designer receptors

Engineered signaling proteins permit precise modulation of cell signaling networks and are valuable tools for basic and translational research. In this issue of Structure, Tichy and colleagues leverage high-resolution GPCR-G protein complex structures to rationally design improved light-activated chimeric GPCRs (termed OptoXRs) with increased sensitivity and tunable signaling features

Structural Insights Accelerate the Discovery of Opioid Alternatives

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the mu -opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein-coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents

The structure, function, and pharmacology of MRGPRs

Mas-related G protein-coupled receptor (MRGPR) family members play important roles in the sensation of noxious stimuli and represent novel targets for the treatment of itch and pain. MRGPRs recognize a diversity of agonists and display complicated downstream signaling profiles, high sequence diversity across species, and many polymorphisms in humans. The recent structural advances on MRGPRs reveal unique structural features and diverse agonist recognition modes of this receptor family, which should facilitate the structure-based drug discovery at MRGPRs. In addition, the newly discovered ligands also provide valuable tools to explore the function and the therapeutic potential of MRGPRs. In this review, we discuss these progresses in our understanding of MRGPRs and highlight the challenges and potential opportunities for the future drug discovery at these receptors

New Technologies for Elucidating Opioid Receptor Function

Recent advances in technology, including high resolution crystal structures of opioid receptors, novel chemical tools, and new genetic approaches have provided an unparalleled palette of tools for deconstructing opioid receptor actions in vitro and in vivo. Here we provide a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives, as well as their role in neural circuits in vivo. We then show how insights into the molecular details of opioid actions can facilitate the creation of functionally selective (biased) and photoswitchable opioid ligands. Finally, we describe how newly engineered opioid receptor-based chemogenetic and optogenetic tools, and new mouse lines, are expanding and transforming our understanding of opioid function and, perhaps, paving the way for new therapeutics. © 2016 Elsevier Ltd. All rights reserved

Mining the receptorome

[No abstract available