Molecular Pharmacology of Metabotropic Receptors Targeted by Neuropsychiatric Drugs
Total Page：16
File Type：pdf, Size：1020Kb
Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs Bryan L. Roth Metabotropic receptors are responsible for so-called ‘slow synaptic transmission’ and mediate the effects of hundreds of pep- tide 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, elucidat- ing 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. eurotransmitter receptors are essential for mediating the GPCRs, which have complex actions mediated by second messen- effects of neurotransmitters in the brain and peripheral gers and protein kinases21,22 (Fig. 1). Nnervous system. There are generally considered to be two This Review will discuss how structural insights into neurotrans- types of neurotransmitter receptors: ionotropic and metabotropic. mitter GPCRs have transformed the understanding of these recep- While ionotropic receptors are typically ligand-gated ion chan- tors, focusing on example GPCRs that are targets of drugs approved nels, through which ions pass in response to a neurotransmitter, for use in the treatment of neuropsychiatric disorders. The past metabotropic receptors need G proteins and second messengers to decade has witnessed remarkable progress in elucidating the struc- indirectly modulate ionic activity in neurons. G protein–coupled ture and function of GPCR family, with perhaps 60 or so GPCRs receptors (GPCRs) represent the largest family of metabotropic having their structures determined by X-ray crystallography7 or receptors, although receptor tyrosine kinases1 and guanylate cyclase cryo-EM7. Additionally, various intermediate signaling states, receptors2,3 can also be considered metabotropic receptors4. GPCRs ranging from inactive to active, have been elucidated for exem- also constitute the largest family of druggable targets5,6 encoded by plar GPCRs6. Finally, progress has been made on the use of such the human genome, and 34% of medications approved by the US structural information for structure-guided and structure-inspired Food and Drug Administration have GPCRs as their main thera- neuropsychiatric drug discovery8. This Review will provide an over- peutic target7,8, especially those used for the treatment of neuropsy- view of the understanding of how structure informs the function chiatric disorders6,9,10 (Table 1). of representative neurotransmitter GPCRs. It will also show how There are many distinct chemical classes of neurotransmitters, an understanding of structure elucidates neuropharmacology and including the following: (1) small molecules (e.g., glutamate, nor- will highlight therapeutic challenges and opportunities for neuro- epinephrine and serotonin); (2) neuropeptides (e.g., enkephalins, transmitter-targeted GPCRs. endorphins and neurokinins); and (3) others, including metabolites (e.g., endocannabinoids, ATP, ADP and adenosine) and gases (e.g., Structural genomics of neurotransmitter-targeted GPCRs nitric oxide). Although the precise number of brain neurotransmit- Structural genomics has been defined as the approach that proposes ters is not known with certainty, it is likely that hundreds of distinct ‘determining protein structures on a genome-wide scale’23, which neurotransmitters exist, including many ‘orphan’ neuropeptides11. boils down to ultimately determining the three-dimensional struc- Each neurotransmitter system has distinct cellular and region-spe- ture of every protein encoded by the human genome. Obtaining cific distribution patterns in the brain; these can be visualized at the GPCR structures has been historically challenging. Thus, although mRNA level with the Allen Brain Atlas12 or via genetically encoded low-resolution structures of rhodopsin were available as early as markers with the GENSAT (Gene Expression Nervous System 1993 (ref. 24), and useful models of helical arrangements were gen- Atlas) resource13. Almost all neurotransmitters transduce their sig- erated through the use of that information25, the first bona fide nals at least in part by activating GPCRs, and the regional and cellu- high-resolution GPCR structure was not achieved until 2000, with lar distributions of brain GPCR mRNAs are well described12,14. As is rhodopsin26. The first non-opsin GPCR structures were obtained the case with neurotransmitters, each of the metabotropic receptors in 2007 (refs. 27–29), and since then, structures have been obtained, for neurotransmitters has a distinct regional and cellular distribu- mainly via X-ray crystallography, for around 60 distinct human tion in the brain12,14 and elsewhere14. GPCRs7 (Fig. 2a). To generate useful structures, GPCR crystallog- GPCRs modulate synaptic transmission via so-called ‘slow raphy typically requires high-affinity ligands, which serve to stabi- synaptic transmission’15, which occurs in a time frame of seconds lize the receptor in a distinct state suitable for crystallography. Such to minutes in the central nervous system. Metabotropic receptors compounds not only need to be of high affinity (e.g., in the low such as GPCRs may be found pre- and post-synaptically. Pre-synaptic nanomolar to picomolar range) but also need to have slow dissocia- 30 Gi-coupled GPCRs, such as the 5-HT1A and 5-HT1B serotonin tion rates . Ideally, then, to obtain complete structural coverage of receptors16,17, inhibit neurotransmitter release via Gβ/γ-mediated all GPCRs encoded by the human genome, one would need high- activation of inhibitory channels, such as G protein–coupled affinity, slowly dissociating ligands for each of them. Such ligands inwardly rectifying potassium channels18, and via the inhibition of do not necessarily need to be specific, as, for example, the non- vesicle-docking SNARE-like proteins19,20 (Fig. 1). Post-synaptically, selective drug ergotamine has been used to obtain the structures of 31 GPCRs can enhance neuronal excitability via Gs- and Gq-coupled three different serotonin receptor subtypes: 5-HT1B (ref. , 5-HT2B Department of Pharmacology, University of North Carolina Chapel Hill, School of Medicine, Chapel Hill 27514 NC, USA. e-mail: [email protected] Table 1 | Representative metabotropic neurotransmitter receptors as targets for neuropsychiatric disorders and drugs of abuse T arget class Neurotransmitter Receptor Representative Therapeutic indications or Pharmacological Structure medication abuse action determined (ref.) GPCR Dopamine D2 dopamine Ropinirole Parkinson’s Disease Agonist 75 GPCR Dopamine D2 dopamine Nemonapride Schizophrenia Antagonist/ 75 inverse agonist GPCR Serotonin 5-HT2C serotonin Lorcaserin Obesity Agonist 33 GPCR Serotonin 5-HT1A serotonin Buspirone Anxiety and depression Partial agonist None reported GPCR Serotonin 5-HT1B Ergotamine Migraine headaches Antagonist 31,32 GPCR Adenosine A2A adenosine Caffeine Alertness Antagonist 131 GPCR Norepinephrine β1 and β2 Propranolol Post-traumatic stress Inverse agonist 132,133 adrenergic disorder; anxiety disorders GPCR Serotonin 5-HT2A serotonin Pimavanserin Psychosis related to Inverse agonist 134 Parkinson’s Disease GPCR Serotonin Many 5-HT LSD Hallucinogen use and Agonist 70 receptors abuse GPCR Endocannabinoids CB1 cannabinoid Tetrahydrocannibinol Anorexia related to cancer Agonist 135 chemotherapy; cannabis abuse GPCR GABA GABA-B Baclofen Spasticity-related Agonist None reported movement disorders GPCR Histamine H1-histamine Diphenhydramine Sedative Antagonist 41 GPCR Endorphins; μ-opioid Morphine Pain; abused opioid Agonist 59,136 endomorphans GPCR Dynorphin κ-opioid Nalfurafine Itch Agonist 52,137 GPCR Dynorphin κ-opioid Salvinorin A Hallucinogen use and Agonist 52,137 abuse GPCR Orexin OX1 orexin Suvorexant Insomnia Antagonist 138 GPCR Norepinephrine α2 adrenergic Clonidine Anxiety; opioid withdrawal Agonist None reported GPCR S1P1 sphingosine Fingolimod Multiple sclerosis Downregulates 139 antagonist receptor Receptor Nerve growth TRK Entrectinib Cancers including Antagonist No full-length tyrosine factors astrocytoma structure kinase reported Guanylate Atrial natriuretic NPRA atrial Atrial natriuretic None (heart failure) Agonist 140 cyclases peptide natriuretic receptor peptide GABA, γ-amino butyric acid. 32 33 40 (ref. ) and 5-HT2C (ref. ). Once structures are obtained, even with ligand-free state has been solved —those GPCRs for which there non-selective ligands, the structural features for distinct pharmaco- are reported structures typically have hundreds to thousands of logical properties can be elucidated (as in refs. 32,33). Furthermore, annotated ligands (Fig. 2a). No clear relationship exists between obtaining structures of related GPCRs frequently facilitates the the number of annotated ligands in Chembl and the number structure-guided discovery and design of subtype-selective drugs34. of distinct structures (Fig. 2b), although, as mentioned above, An analysis of available GPCR structures and cognate ligands, high-affinity, slowly dissociating ligands are typically key for done with open-source databases of small molecules that bind obtaining structures. Thus, comprehensive elucidation