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Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties

Nature Neuroscience volume 25, pages 39–49 (2022)Cite this article

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Abstract

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected ‘upside-down’ pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a ‘bolt’. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

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Fig. 1: Overall architecture of 5-HT2AR bound to aripiprazole.
Fig. 2: The exosite determines the efficacy of aripiprazole at DRD2 and 5-HT2AR.
Fig. 3: Comparison of exosite residues between 5-HT2AR and DRD2.
Fig. 4: Structure-guided design of selective DRD2 partial agonist.
Fig. 5: The antipsychotic-like efficacy of (–)-IHCH7041 in rodent animal models.
Fig. 6: (–)-IHCH7041 alleviates learning and memory impairments and cognitive disturbance induced by subchronic MK-801 treatment.

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Data availability

The structural files have been deposited on the RCSB PDB database with the PDB codes 7VOE and 7VOD. All related source data are publicly available.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (grant no. 2020YFA0509600), the National Natural Science Foundation of China (NSFC) (grant no. 32071197), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB19020111), Shanghai Science and Technology Committee (grant no. 19ZR1466200), the Thousand Talents Plan-Youth and Shanghai Rising-Star Program (grant no. 20QA1410600) to S.W.; and by the NSFC (grant no. 81703361), Shanghai Science and Technology Committee (grant no. 20S11901200), Shanghai Municipal Government and ShanghaiTech University to J.C. The diffraction data were collected at BL45XU and BL41XU of SPring-8 (JASRI proposal nos. 2020A2715 and 2020A2605). We thank K. Hirata, Y. Nakamura and K. Hasegawa for their help with data collection. We thank Z. Yang for her help with molecular docking. The Ki determinations of receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract no. HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by B. L. Roth at the University of North Carolina at Chapel Hill, and by Project Officer J. Driscoll at NIMH, Bethesda, MD, USA.

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Author notes

  1. These authors contributed equally: Zhangcheng Chen, Luyu Fan, Huan Wang, Jing Yu, Dengyu Lu.

Authors and Affiliations

  1. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

    Zhangcheng Chen, Luyu Fan, Jing Yu, Jianzhong Qi, Fen Nie & Sheng Wang

  2. iHuman Institute, ShanghaiTech University, Shanghai, China

    Huan Wang & Jianjun Cheng

  3. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technolog, Chinese Academy of Sciences, Shanghai, China

    Dengyu Lu & Zhen Liu

  4. Institute of Molecular Enzymology, Soochow University, Suzhou, China

    Zhipu Luo

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Contributions

Z.C. expressed the protein, purified the receptor, optimized crystallization conditions, grew crystals for data collection, collected diffraction data, performed ligand binding and functional assays, analyzed all data and assisted with preparing the manuscript. L.F. performed pharmacological assays, analyzed the data and assisted with preparing the manuscript. H.W. synthesized analogs and performed the analytical chemical analysis. J.Y. performed in vivo studies and analyzed the data. D.L. performed the in vitro slice electrophysiological recordings. F.N. performed the GPCRome assay and analyzed the data. J.Q. assisted with in vivo studies. Z. Luo provided independent structure quality control analysis and assisted with structure determination. Z. Liu supervised the slice electrophysiological recordings. J.C. supervised ligand design and synthesis, and edited the manuscript. S.W. was responsible for the overall project strategy, solved and analyzed the structure and management, and wrote the manuscript.

Corresponding authors

Correspondence to Jianjun Cheng or Sheng Wang.

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Extended data

Extended Data Fig. 1 Differential pharmacological behaviours of the TGAs at 5-HT2AR and DRD2.

a, Chemical structures of aripiprazole, brexpiprazole, and cariprazine. b-m, Concentration-response curves for: b-g, the Gαi-γ dissociation at DRD2; h-i, the β-arrestin1/2 recruitment at DRD2; j-k, the Gαq/11-γ9 dissociation at 5-HT2AR; and l-m, the β-arrestin1/2 recruitment at DRD2. EC50 and Emax values are shown in Supplementary Table 6. In all panels, n = 3 independent experiments, error bars represent SEM.

Source data

Extended Data Fig. 2 Unique binding pose of TGAs in 5-HT2AR and DRD2.

a, The introduced S3727.45N mutation substantially enhances purification yield. b, Electron density maps of aripiprazole and cariprazine. Fo-Fc omit maps were calculated by polder map. c, Overall view of 5-HT2AR/Cariprazine complex structure. Cariprazine is shown as sticks overlaid with transparent spheres. d, Conformational changes between 5-HT2AR/Aripiprazole and 5-HT2AR/25CN-NBOH (active, PDB code: 6WHA) are magnified at four key representative motifs. Conformations of these microswitches in the 5-HT2AR/Aripiprazole structure resemble the inactive states of 5-HT2AR/Risperidone (PDB code: 6A93). e, Alignment of OBPs across family A GPCRs. Aripiprazole and cariprazine stretch to a one-helix turn deeper position below W6.48. Ligands are represented as spheres.

Source data

Extended Data Fig. 3 The binding pose of cariprazine in 5-HT2AR and docking poses of TGAs in DRD2.

a, Top extracellular view of cariprazine and the OBP of 5-HT2AR. b, Schematic of cariprazine- binding residues at a 4.0 Å cut-off. The hydrogen bond between D1553.32 and cariprazine’s basic nitrogen is shown as grey dashed line. Primary and secondary pharmacophore and linker are indicated. c, 2Fo-Fc electron density map of 5-HT2AR exosite-related residues (blue mesh) contoured at 1σ. d, Overlay of DRD/Risperidone (PDB code: 6CM4) with two docked DRD2/Aripiprazole poses. The induced-fit docking with side chain configurations of F2435.47, F2445.48, and F3406.52 corrected recaptures aripiprazole’s binding pose in 5-HT2A/Aripiprazole crystal structure. e, Two different binding poses of cariprazine illustrated in rigid and induced-fit docking models of DRD2. In all panels, the Ballesteros-Weinstein numbering is shown as superscript.

Extended Data Fig. 4 Residue at 5.51 position plays a vital role in determining signalling transduction efficacies.

a, Sequence alignment of the OBP and exosite amino acid residues between DRD2 and 5-HT2AR. b-g, Testing pharmacology of the three TGAs at 5-HT2AR via Gαq-γ9 dissociation and β-arrestin2 recruitment assay and consequent effects of 5.51 mutations when L5.51 mutated into alanine [A], valine [V], or phenylalanine [F]. h-k, assays were set as in b-g but for DRD2. In all panels, n = 3 independent experiments, error bars represent SEM. l, m, Cell surface expression levels of wild-type and 5-HT2AR / DRD2 mutants measured by NanoLuc system (see Methods). WT, wild-type receptor. n = 4 independent experiments performed in quadruplicate replicates.

Source data

Extended Data Fig. 5 The pharmacological profiles of compound 34 at wild-type and 5.51 mutants of DRD2.

a, Synthesis of compound 34 via modification of secondary pharmacophore (SP, highlighted in light blue). A smaller benzothiazole group in compound 34 means a longer interaction distance between SP and F5.51 in DRD2. b, c, Gαi1-γ9 dissociation and β-arrestin2 recruitment assay show a decreased Emax of compound 34 compared to aripiprazole. d, e, Mutating F5.51 into alanine [A], leucine [L], or tyrosine [Y] and consequent effects on compound 34’s pharmacological behaviour as evaluated by Gαi1-γ9 dissociation and β-arrestin2 recruitment assay. WT, wild-type receptor. In panels b-e, n = 3 independent experiments, error bars represent SEM.

Source data

Extended Data Fig. 6 (–)-IHCH7041 shows selective partial agonism at D2-like receptors.

a, Binding affinities of (–)-IHCH7041 to endogenous receptors, channels, and transporters. The values are shown in Supplementary Table 5. b, (–)-IHCH7041 at 1 μM was screened against 320 non-olfactory GPCRs for agonism in the arrestin recruitment TANGO assay. Each point shows luminescence normalized to basal level at a given GPCR. Data are mean ± SEM of normalized fold change. c-g, Receptors with over 2-fold response were further evaluated by concentration-response-curves in the arrestin recruitment TANGO assay. n = 3 independent experiments, error bars represent SEM.

Source data

Extended Data Fig. 7 The pharmacological profiles of (–)-IHCH7041 at DRD2, DRD3 and 5-HT1AR.

a, Heatmap illustration of transduction coefficients of three TGAs and (–)-IHCH7041 at DRD2, DRD3 and 5-HT1AR. b, Concentration–response curves demonstrating the abilities of three TGAs and (–)-IHCH7041 to activate DRD2, DRD3 and 5-HT1A receptors, EC50 and Emax values are shown in Supplementary Tables 6–8. All data were generated from BRET experiments, n = 3 independent experiments, error bars represent SEM.

Source data

Extended Data Fig. 8 In vivo characterization of (–)-IHCH7041’s pharmacokinetics and antipsychotic-like properties.

a, Metabolic rate of (–)-IHCH7041, n = 3 mice. b, Brain penetration of (–)-IHCH7041, n = 3 mice. c, d, Locomotor responses in mice are shown as 5-min binned intervals (c) or 0- to 45-min time interval (d) to the vehicle or different doses of aripiprazole followed 30 min later by 0.2 mg/kg MK-801. n = 8 mice per group. e, Bar graph of distance travelled after MK-801 administration (0- to 45-min time interval, Related Fig. 5a). f, (–)-IHCH7041(10 mg kg−1) and three TGAs (10 mg/kg) do not elicit recognizable catalepsy; haloperidol (2 mg kg−1) is used as the positive control to elicit catalepsy as assessed by latency to movement. Compounds were administered i.p. 60 min before the test. n = 8 mice per group. g, Evaluation of effects of (–)-IHCH7041 on learning and memory performance of mice subjected to subchronic MK-801 treatment (Related Fig. 6b). Latency to find the platform among (–)-IHCH7041 (0.00625, 0.025 or 0.1 mg kg−1), aripiprazole (3 mg kg−1), or vehicle groups was accessed by Morris water maze test in the acquisition phase. Compounds were injected i.p. 30 mins before each acquisition trial. n = 8 mice per group. In all panels, error bars, SEM. Veh, vehicle. *P < 0.05 and **P < 0.01 (Two-way ANOVA); specific statistical tests, information on reproducibility, and exact P values are reported in Methods and in Source data.

Source data

Extended Data Fig. 9 Antidepressant-like property of (–)-IHCH7041 in mouse models of depression.

a, Locomotor responses in male mice are shown as 5-min binned intervals to vehicle or different doses of (–)-IHCH7041 treatment 30 min prior to 6 mg/kg amphetamine i.p. injection. b, Bar graph of distance travelled after MK-801 administration (0- to 45-min time interval) and the calculation of ED50. c, Inhibition of hyperlocomotion by (–)-IHCH7041 in female mice. d, Antidepressant-like activity of (–)-IHCH7041 (0.4 mg kg−1) was accessed by forced swim test (FST) and its blockade by 5-HT1AR-selective antagonist WAY-100635 (10 mg kg−1), DRD2 antagonist haloperidol (0.2 mg kg−1) or DRD3-selective antagonist SB-277011 (10 mg kg−1) in mice exposed to acute restraint stress (ARS). e, Antidepressant activity of (–)-IHCH7041 was accessed by tail suspension test (TST), aripiprazole (3 mg kg−1) was tested in parallell in mice exposed to ARS. f, Antidepressant activity of (–)-IHCH7041 (0.4 mg kg−1) was accessed by TST and its blockade by 5-HT1AR-selective antagonist WAY-100635 (10 mg kg−1), DRD2 antagonist haloperidol (0.2 mg kg−1) or DRD3-selective antagonist SB-277011 (10 mg kg−1) in mice exposed to ARS. g, Antidepressant activity of (–)-IHCH7041 (0.4 mg kg−1) in corticosterone (Cort)-induced depression-like model and its blockade by 5-HT1AR-selective antagonist WAY-100635 (10 mg kg−1). Ketamine (10 mg kg−1) was used as an antidepressant control in (d), (f), and (g). n = 8 mice in panels a, c, e, and n = 10 mice in panels d, f, g, female mice are symbolled as filled grey circles in panels d, f, g, error bars represent SEM. Veh, vehicle. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001 (two-tailed unpaired t-tests); specific statistical tests, information on reproducibility, and exact P values are reported in Methods and in Source data.

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Extended Data Fig. 10 Cognitive, learning, and memory impairments imposed by sub-chronic administration of MK-801 and its reversal by (–)-IHCH7041.

a, In Novel object recognition (NOR) test, injection of single dose of (–)-IHCH7041 (0.1 mg kg−1) reversed cognitive impairment. The cognition recovery effect of (–)-IHCH7041 was blocked by 5-HT1AR selective antagonist WAY-100635 (10 mg kg−1) but not by DRD2 or DRD3 antagonist, that is, haloperidol (0.2 mg kg−1) or SB-277011 (10 mg kg−1). b, c, In Morries water maze (MWZ) test, the learning and memory recovery effect of (–)-IHCH7041 was blocked by 5-HT1AR selective antagonist WAY-100635 (10 mg kg−1), but not by DRD2 or DRD3 antagonist, that is, haloperidol (0.2 mg kg−1) or SB-277011 (10 mg kg−1) both in acquisition phase (c) and probe phase (b). d, Sample trace showing evoked firing of mPFC layer 2/3 pyramidal neurons before and after bath application of (–)-IHCH7041 (10 μM). e, WAY-100635 (20 μM) blocked spiking-inhibitory effect of (–)-IHCH7041, n = 6 neurons from 3 mice. In panels a, b, and c, n = 8 mice. error bars in all panels represent SEM. Veh, vehicle. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001 (two-tailed unpaired t-tests in (a) and (b), two-way ANOVA in (c) and (e)); specific statistical tests, information on reproducibility, and exact P values are reported in Methods and in Source data.

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Supplementary Tables 1–8 and supplementary protocols of chemical synthesis

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Chen, Z., Fan, L., Wang, H. et al. Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties. Nat Neurosci 25, 39–49 (2022). https://doi.org/10.1038/s41593-021-00971-w

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