Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures

Abstract

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT_2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT_1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.

Keywords: G protein-coupled receptors; cryo-electron microscopy; major depressive disorder; novel antidepressants; structure-based drug design; virtual drug screening.

Figure 5

Molecular mechanism of the rapid antidepressant effect of ketamine. (A). Overexpression of the potassium channel Kir4.1 on the astrocyte during depression leads to a decrease in the concentration of K⁺ in the cell’s interstitial space [57,58]. Along with NMDAR and T-SVCC promoting Ca²⁺ inward flow, this leads to clustered firing of LHb neurons and oversuppression of downstream reward nuclei. In contrast, antagonism of NMDAR by ketamine abolished the abnormal cluster discharge and restored normal Ca²⁺ inward flow and action potential. (B). Ketamine inhibits GABA release by antagonizing NMDAR on inhibitory GABAergic interneurons, which leads to the withdrawal of its inhibitory effect on glutamatergic excitatory neurons [257,258,259]. Ketamine blocking NMDAR-mediated Ca²⁺ inflow is represented by ✕ symbol. Direct antagonism of the NMDAR on the postsynaptic membrane produces an inhibitory effect on eEF2 [60,260]. In addition, antagonism of the extrasynaptic NMDAR activates the mTORC pathway, promoting PSD-enriched protein expression and enhanced synaptic plasticity [265]. Activation of AMPAR plays a necessary role in the antagonism of NMDAR by R-HNK to produce antidepressant effects [60,260]. The transmembrane helix of TrkB can bind R-HNK and activate downstream synaptic plasticity signaling pathways via dimerization [134]. (C). NMDAR binding S-ketamine cryo-EM structure [26]. NMDAR is a tetramer composed of two N1 subunits (gray) and two N2 subunits (green) (left). The different composition of N2 subunits determines the type of NMDAR. One conformation of S-ketamine localized in vestibule is shown (right) [PDB: 7EU7].

Figure 1

Key neural circuits in MDD. Reward circuitry: NAc integrates excitatory neurotransmission from HPC and mPFC to regulate emotions (process 1). The VTA-NAc dopaminergic pathway displays antidepressant-like properties (process 2). LHb is linked to aversion and depressive states, stimulating RMTg, which inhibits VTA dopaminergic neurons. LHb also directly suppresses the reward centers VTA and DRN (process 3). 5-HTrgic neurons project from DRN to mPFC: the activation of 5-HT_1A autoreceptors in the DRN reduce serotonergic neuron activity, leading to decreased 5-HT release in the mPFC (process 4). The types of neurons in circuits are distinguished by the color of the arrows and shown at the top left. The arrows of excitatory projection are triangular, and inhibitory projection are prismatic. Abbreviations: PFC, prefrontal cortex; NAc, nucleus accumbens; HPC, hippocampus; VTA, ventral tegmental area; RMTg, rostromedial tegmental nucleus; LHb, lateral habenula; DRN, dorsal raphe nucleus.

Figure 2

Affinity and structural results of psychedelics for GPCRs. (A). Three chemical types of psychedelics with different receptor binding affinities. LSD broadly activates multiple 5-HT receptor subtypes with high affinity (receptor affinity > 8.0, displayed in orange) and dopamine receptors (DRs). The two indoleamines have a low affinity, and the two phenylalkylamines have a high affinity for 5-HT₂ receptors. Data from ChEMBL (https://www.ebi.ac.uk/chembl, accessed on 1 November 2023), receptor affinity = pKi. Abbreviations: LSD: lysergic acid diethylamide, 5-MeO-DMT: 5-methoxy-N,N-dimethyltryptamine, DOI: 2,5-Dimethoxy-4-iodoamphetamine, DOB: 4-Bromo-2,5-dimethoxyamphetamine. (B). Phylogenetic tree of aminergic GPCRs, GPCR cluster based on sequence similarity. The 5-HT receptors–coupled G protein subtypes are displayed as dots, and the combinations that have been resolved are represented as stars. (C). Cryo-EM and X-ray resolved growth trends of all and activated GPCRs (2017–2022). (B,C) data from GPCR DB (https://gproteindb.org, accessed on 1 November 2023).

Figure 3

Structure–function mechanism of psychedelic activation of 5-HT_2A receptor. (A). 5-HT_2A receptor binds an agonist, 25CN-NBOH [green, PDB: 6WHA], and an inverse agonist, methiothepin [gray, PDB: 6WH4], exhibiting active and inactive conformations, respectively [24]. The active conformation of 5-HT_2A receptors TM5 and TM6, moving outward, and ICL2, transitioning from a free loop to an incomplete helix. The details in the dashed line box are shown on the right, the same below. (B). 5-HT_2B receptor snapshots of linked β-arrestin [green, PDB: 7SRS] and Gq [gray, PDB: 7SRR] [97]. Embedding Gq and β-arrestin relies on the outward mobility of TM5 and TM6. β-arrestin, leads to more significant outward movement, accompanied by a downward shift of helix 8 (H8). (C). LSD [yellow, PDB: 7WC6] occupies both the OBP and EBP, contacting key residues S5.64 and W3.28 in both pockets, respectively. IHCH-7086 [red, PDB: 7WC9] is mainly located in the SEP pocket, while the other pharmacophore avoids the OBP, leaving room for lipid occupancy [25,165]. Most of the body of R-69 [blue, PDB: 7RAN] is in the OBP and does not contact W3.28.

Figure 4

Schematic diagram of antidepressant molecules acting on the 5-HT system. (A). From left to right, they are as follows: SSRI increases 5-HT concentration in the synaptic gap by antagonizing. SERT blocks the reuptake of 5-HT into the presynaptic membrane. MAOIs reduce the deactivation of 5-HT after oxidation reaction by inhibiting MAO activity. IHCH-7086 recruits β-arrestin through functionally selective and mild activation of 5-HT_2A receptors, thereby removing hallucinogenic activity [25]. R-69 activates 5-HT_2A receptor with high affinity and specificity, with a bias toward activation of Gq [165]. IHCH-7041 selectively binds DRD2 and 5-HT_1A receptor but not 5-HT_2A receptor. [233]. NLX-204 highly selectively activates the postsynaptic 5-HT_1A receptor of mPFC without binding to the 5-HT_1A autoreceptor of DRN [249]. Psychedelics activate intracellular (especially endoplasmic reticulum) 5-HT_2A receptor and enhance synaptic plasticity [71]. (B). ZZL-7 facilitates the translocation of SERT to the plasma membrane by disrupting the linkage between nNOS and SERT [253]. This leads to a decrease in extracellular 5-HT concentration. The 5-HT_1A autoreceptor activation located in the DRN is inhibited, thereby abolishing the inhibition of the mPFC projection impulse.

Figure 6

Landmark events in the discovery and utilization of psychedelics. The representative psychedelics are found in the white box. The structural discoveries are shown in blue boxes. The development of novel antidepressant molecules is shown in pink boxes.