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

Dr. Roth replies

[No abstract available

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

A Structural Understanding of Class B GPCR Selectivity and Activation Revealed

Ma et al. (2020) and Liang et al. (2020) describe the cryo-EM structures of three class B G protein-coupled receptors (GPCRs) in complex with native peptides and Gs. Their work establishes the structural basis of peptide specificity and a conserved mechanism of receptor activation and G protein coupling for class B GPCRs. Ma et al. (2020) and Liang et al. (2020) describe the cryo-EM structures of three class B G protein-coupled receptors (GPCRs) in complex with native peptides and Gs. Their work establishes the structural basis of peptide specificity and a conserved mechanism of receptor activation and G protein coupling for class B GPCRs

Chemogenetics-a transformational and translational platform

Neurologic disorders are frequently a result of inappropriate electrical and/or chemical signaling of neurons and glia. Ultimate remediation would necessitate reprogramming these signals. Historically, correcting neuronal and glial signaling is accomplished via drug therapy/administration, although they frequently fail to effectively and fully treat the underlying disorder. Developments in basic research have produced several new classes of potential therapeutics to directly and precisely control neuron activity at the single-cell level. We review one such technology, Designer Receptors Exclusively Activated by Designer Drugs, and suggest its potential as a powerful tool for augmenting neuronal and glial signaling and activity for basic and translational applications. Copyright 2015 American Medical Association. All rights reserved

A self-activating orphan receptor

[No abstract available

Lorcaserin and pimavanserin: Emerging selectivity of serotonin receptor subtype-targeted drugs

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively