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Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs

Nature Structural & Molecular Biology volume 26, pages 535–544 (2019)Cite this article

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Abstract

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.

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Fig. 1: Metabotropic receptors such as GPCRs modulate synaptic transmission.
Fig. 2: The availability of chemical matter is useful for obtaining GPCR structures.
Fig. 3: Structural validation of the extended ternary complex model of GPCR action.
Fig. 4: Structural rearrangements associated with distinct GPCR states.
Fig. 5: Structure-guided design of selective GPCR ligands for dopaminergic modulating neurotransmission.
Fig. 6: Structure-inspired design of ligands for GPCRs to modulate synaptic transmission.

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Acknowledgements

The author thanks W. Kroeze for editing and comments. Work described in this Review was funded by grants and contracts from the US National Institute of Health as well as the Michael Hooker Distinguished Professorship.

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  1. Department of Pharmacology, University of North Carolina Chapel Hill, School of Medicine, Chapel Hill, 27514, NC, USA

    Bryan L. Roth

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Roth, B.L. Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs. Nat Struct Mol Biol 26, 535–544 (2019). https://doi.org/10.1038/s41594-019-0252-8

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