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

Focus on research: Drugs and valvular heart disease

[No abstract available

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

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

Psychedelics: preclinical insights provide directions for future research

Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology, pharmacology, and structural biology in an attempt to reveal both the knowns and unknowns within the field

The cranial windows of perception

Psilocybin has emerged as a potentially rapidly acting antidepressant with enduring actions. In this issue of Neuron, Shao et al. (2021) show that psilocybin quickly induces dendritic spine formation in cortical layer V pyramidal neurons. These results provide a potential cellular substrate for psilocybin's therapeutic actions

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

Sensing unsaturated fatty acids: insights from GPR120 signaling

GPR120 is a receptor that plays a crucial role in mediating the beneficial effects of free fatty acids (FAs), particularly ω-3 FAs, on metabolic and inflammatory pathways, making it an important therapeutic target for metabolic diseases. Recently, Mao et al. report the cryo-EM structures of GPR120 in complex with an ω-3 FA as well as other three endogenous FAs and a synthetic agonist, along with pharmacological investigations and molecular dynamics simulations, thereby providing comprehensive insights into the molecular recognition and biased signaling of GPR120 via various agonist