Target Information
| Target General Information | Top | |||||
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| Target ID |
T69685
(Former ID: TTDC00227)
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| Target Name |
Glycine transporter GlyT-1 (SLC6A9)
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| Synonyms |
Solute carrier family 6 member 9; Sodium- and chloride-dependent glycine transporter 1; Glycine type-1 transporter; Glycine transporter type 1; GlyT1; GlyT-1
Click to Show/Hide
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| Gene Name |
SLC6A9
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Schizophrenia [ICD-11: 6A20] | |||||
| Function |
May play a role in regulation of glycine levels in NMDA receptor-mediated neurotransmission. Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Click to Show/Hide
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| BioChemical Class |
Neurotransmitter:sodium symporter
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| UniProt ID | ||||||
| Sequence |
MSGGDTRAAIARPRMAAAHGPVAPSSPEQVTLLPVQRSFFLPPFSGATPSTSLAESVLKV
WHGAYNSGLLPQLMAQHSLAMAQNGAVPSEATKRDQNLKRGNWGNQIEFVLTSVGYAVGL GNVWRFPYLCYRNGGGAFMFPYFIMLIFCGIPLFFMELSFGQFASQGCLGVWRISPMFKG VGYGMMVVSTYIGIYYNVVICIAFYYFFSSMTHVLPWAYCNNPWNTHDCAGVLDASNLTN GSRPAALPSNLSHLLNHSLQRTSPSEEYWRLYVLKLSDDIGNFGEVRLPLLGCLGVSWLV VFLCLIRGVKSSGKVVYFTATFPYVVLTILFVRGVTLEGAFDGIMYYLTPQWDKILEAKV WGDAASQIFYSLGCAWGGLITMASYNKFHNNCYRDSVIISITNCATSVYAGFVIFSILGF MANHLGVDVSRVADHGPGLAFVAYPEALTLLPISPLWSLLFFFMLILLGLGTQFCLLETL VTAIVDEVGNEWILQKKTYVTLGVAVAGFLLGIPLTSQAGIYWLLLMDNYAASFSLVVIS CIMCVAIMYIYGHRNYFQDIQMMLGFPPPLFFQICWRFVSPAIIFFILVFTVIQYQPITY NHYQYPGWAVAIGFLMALSSVLCIPLYAMFRLCRTDGDTLLQRLKNATKPSRDWGPALLE HRTGRYAPTIAPSPEDGFEVQPLHPDKAQIPIVGSNGSSRLQDSRI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 11 Clinical Trial Drugs | + | ||||
| 1 | BI 425809 | Drug Info | Phase 3 | Schizophrenia | [2] | |
| 2 | Iclepertin | Drug Info | Phase 3 | Schizophrenia | [3] | |
| 3 | R1678 | Drug Info | Phase 3 | Schizophrenia | [4], [5] | |
| 4 | AMG 747 | Drug Info | Phase 2 | Schizophrenia | [6] | |
| 5 | ORG-25935 | Drug Info | Phase 2 | Psychotic disorder | [7] | |
| 6 | PF-3463275 | Drug Info | Phase 2 | Schizophrenia | [8] | |
| 7 | ALX-5407 | Drug Info | Phase 1 | Schizophrenia | [9], [10] | |
| 8 | DCCCyB | Drug Info | Phase 1 | Schizophrenia | [11] | |
| 9 | GlyT1 PET radiotracers | Drug Info | Phase 1 | Schizophrenia | [12] | |
| 10 | JNJ-17305600 | Drug Info | Phase 1 | Schizophrenia | [13] | |
| 11 | MK-2637 | Drug Info | Phase 1 | Schizophrenia | [14] | |
| Patented Agent(s) | [+] 2 Patented Agents | + | ||||
| 1 | PMID29338548-Compound-13 | Drug Info | Patented | Schizophrenia | [15] | |
| 2 | PMID29338548-Compound-21 | Drug Info | Patented | Schizophrenia | [15] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | GSK1018921 | Drug Info | Discontinued in Phase 1 | Schizophrenia | [16] | |
| Preclinical Drug(s) | [+] 6 Preclinical Drugs | + | ||||
| 1 | Org-24461 | Drug Info | Preclinical | Schizophrenia | [10] | |
| 2 | Organon | Drug Info | Preclinical | Schizophrenia | [17] | |
| 3 | Organon-2 | Drug Info | Preclinical | Schizophrenia | [10] | |
| 4 | Organon-3 | Drug Info | Preclinical | Schizophrenia | [10] | |
| 5 | SSR-103800 | Drug Info | Preclinical | Schizophrenia | [10], [18] | |
| 6 | SSR-504734 | Drug Info | Preclinical | Schizophrenia | [10] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Inhibitor | [+] 42 Inhibitor drugs | + | ||||
| 1 | BI 425809 | Drug Info | [19] | |||
| 2 | Iclepertin | Drug Info | [20] | |||
| 3 | ORG-25935 | Drug Info | [21], [22] | |||
| 4 | PF-3463275 | Drug Info | [21] | |||
| 5 | JNJ-17305600 | Drug Info | [26] | |||
| 6 | PMID29338548-Compound-13 | Drug Info | [15] | |||
| 7 | PMID29338548-Compound-14 | Drug Info | [15] | |||
| 8 | PMID29338548-Compound-15 | Drug Info | [15] | |||
| 9 | PMID29338548-Compound-16 | Drug Info | [15] | |||
| 10 | PMID29338548-Compound-17 | Drug Info | [15] | |||
| 11 | PMID29338548-Compound-18 | Drug Info | [15] | |||
| 12 | PMID29338548-Compound-19 | Drug Info | [15] | |||
| 13 | PMID29338548-Compound-20 | Drug Info | [15] | |||
| 14 | PMID29338548-Compound-21 | Drug Info | [15] | |||
| 15 | PMID29338548-Compound-22 | Drug Info | [15] | |||
| 16 | PMID29338548-Compound-23 | Drug Info | [15] | |||
| 17 | PMID29338548-Compound-24 | Drug Info | [15] | |||
| 18 | PMID29338548-Compound-25 | Drug Info | [15] | |||
| 19 | PMID29338548-Compound-26 | Drug Info | [15] | |||
| 20 | PMID29338548-Compound-27 | Drug Info | [15] | |||
| 21 | PMID29338548-Compound-28 | Drug Info | [15] | |||
| 22 | PMID29338548-Compound-29 | Drug Info | [15] | |||
| 23 | PMID29338548-Compound-30 | Drug Info | [15] | |||
| 24 | PMID29338548-Compound-31 | Drug Info | [15] | |||
| 25 | PMID29338548-Compound-33 | Drug Info | [15] | |||
| 26 | PMID29338548-Compound-34 | Drug Info | [15] | |||
| 27 | PMID29338548-Compound-36 | Drug Info | [15] | |||
| 28 | PMID29338548-Compound-37 | Drug Info | [15] | |||
| 29 | PMID29338548-Compound-38 | Drug Info | [15] | |||
| 30 | PMID29338548-Compound-39 | Drug Info | [15] | |||
| 31 | PMID29338548-Compound-40 | Drug Info | [15] | |||
| 32 | PMID29338548-Compound-41 | Drug Info | [15] | |||
| 33 | PMID29338548-Compound-44 | Drug Info | [15] | |||
| 34 | PMID29338548-Compound-45 | Drug Info | [15] | |||
| 35 | PMID29338548-Compound-46 | Drug Info | [15] | |||
| 36 | PMID29338548-Compound-47 | Drug Info | [15] | |||
| 37 | PMID29338548-Compound-48 | Drug Info | [15] | |||
| 38 | PMID29338548-Compound-49 | Drug Info | [15] | |||
| 39 | AS-1522489-00 | Drug Info | [26] | |||
| 40 | GSK931145 | Drug Info | [26] | |||
| 41 | LY2365109 | Drug Info | [26] | |||
| 42 | RO-4840700 | Drug Info | [26] | |||
| Blocker | [+] 9 Blocker drugs | + | ||||
| 1 | R1678 | Drug Info | [1] | |||
| 2 | ALX-5407 | Drug Info | [10], [23] | |||
| 3 | GSK1018921 | Drug Info | [27] | |||
| 4 | Org-24461 | Drug Info | [10] | |||
| 5 | Organon | Drug Info | [10] | |||
| 6 | Organon-2 | Drug Info | [10] | |||
| 7 | Organon-3 | Drug Info | [10] | |||
| 8 | SSR-103800 | Drug Info | [10] | |||
| 9 | SSR-504734 | Drug Info | [10] | |||
| Modulator | [+] 10 Modulator drugs | + | ||||
| 1 | AMG 747 | Drug Info | [21] | |||
| 2 | DCCCyB | Drug Info | [24] | |||
| 3 | GlyT1 PET radiotracers | Drug Info | [25] | |||
| 4 | MK-2637 | Drug Info | [12] | |||
| 5 | [35S]ACPPB | Drug Info | [28] | |||
| 6 | [3H](R)-NPTS | Drug Info | [29] | |||
| 7 | [3H]GSK931145 | Drug Info | [30] | |||
| 8 | [3H]N-methyl-SSR504734 | Drug Info | [26] | |||
| 9 | [3H]NFPS | Drug Info | [26], [31] | |||
| 10 | [3H]SB-733993 | Drug Info | [30] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: [5-Fluoranyl-6-(oxan-4-yloxy)-1,3-dihydroisoindol-2-yl]-[5-methylsulfonyl-2-[2,2,3,3,3-pentakis(fluoranyl)propoxy]phenyl]methanone | Ligand Info | |||||
| Structure Description | Inward-open structure of human glycine transporter 1 in complex with a benzoylisoindoline inhibitor and sybody Sb_GlyT1#7 | PDB:6ZBV | ||||
| Method | X-ray diffraction | Resolution | 3.40 Å | Mutation | Yes | [32] |
| PDB Sequence |
RGNWGNQIEF
109 VLTSVGYAVG119 LGNVWRFPYL129 CYRNGGGAFM139 FPYFIMLIFC149 GIPAFFMELS 159 FGQFASQGCL169 GVWRISPMFK179 GVGYGMMVVS189 TYIGIYYNVV199 ICIAFYYFFS 209 SMTHVLPWAY219 CNNPWNTHDC229 AGVLDLTHSL259 QRTSPSEEYW269 RLYVLKLSDD 279 IGNFGEVRLP289 LLGCLGVAWL299 VVFLCLIRGV315 VYFTATFPYV325 VLTILFVRGV 335 TLEGAFDGIM345 YYLTPQWDKI355 LEAKVWGDAA365 SQAFYSLGCA375 WGGLITMASY 385 NKFHNNCYRD395 SVIISITNCA405 TSVYAGFVIF415 SILGFMANHL425 GVDVSRVADH 435 GPGLAFVAYP445 EALTLLPISP455 LWSLLFFFML465 ILLGLGTQFC475 LLETLVTAIV 485 DEVGNEWILQ495 KKTYVTLGVA505 VAGFLLGIPL515 TSQAGIYWLL525 LMDNYAASFS 535 LVVISCIMCV545 AIMYIYGHRN555 YFQDIQMMLG565 FPPPLFFQIC575 WRFVSPAIIF 585 FILVFTVIQY595 QPITYNHYQY605 PGWAVAIGFL615 MALSSVLCIP625 LYAMFRLART 635 DGDTLLQRLK645 NATKPSRDWG655 PALLEHRTG
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TYR116
2.594
ALA117
2.564
VAL118
3.355
GLY119
2.027
LEU120
3.231
GLY121
1.840
ASN122
2.615
PHE154
2.908
LEU158
2.597
TYR196
3.337
GLN367
4.744
TYR370
2.663
SER371
2.218
LEU372
3.944
GLY373
2.174
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Synaptic vesicle cycle | hsa04721 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Na+/Cl- dependent neurotransmitter transporters | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | NRF2 pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of Roche (2009). | |||||
| REF 2 | ClinicalTrials.gov (NCT04846868) Clinical Trial of BI 425809 Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1). U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT05211947) An Open Label, Single Arm, Extension Trial to Examine Long-term Safety of Iclepertin Once Daily in Patients With Schizophrenia Who Have Completed Previous Iclepertin Phase III Trials (CONNEX-X). U.S.National Institutes of Health. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7546). | |||||
| REF 5 | ClinicalTrials.gov (NCT01235559) A Study of RO4917838 (Bitopertin) in Patients With Sub-optimally Controlled Symptoms of Schizophrenia (WN25305). U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT01568216) 20101299: Study to Evaluate the Effect of AMG 747 on Schizophrenia Negative Symptoms. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT00725725) Org 25935 Versus Placebo as Augmentation to Cognitive-behavioral Therapy to Treat Panic Disorder (P05705AM3)(TERMINATED). U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT00977522) A Study Of PF-03463275 As Add-On Therapy In Outpatients With Persistent Negative Symptoms Of Schizophrenia. U.S. National Institutes of Health. | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4618). | |||||
| REF 10 | The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. | |||||
| REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029447) | |||||
| REF 12 | Characterization of the novel GlyT1 PET tracer [18F]MK-6577 in humans. Synapse. 2015 Jan;69(1):33-40. | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026554) | |||||
| REF 14 | ClinicalTrials.gov (NCT00934466) Study of the Effect of Single Doses of MK2637 and Dextromethorphan on Cerebral Cortex Excitability (2637-008). U.S. National Institutes of Health. | |||||
| REF 15 | Glycine transporter-1 inhibitors: a patent review (2011-2016).Expert Opin Ther Pat. 2018 Mar;28(3):197-210. | |||||
| REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027678) | |||||
| REF 17 | Receptor binding of allylestrenol, a progestagen of the 19-nortestosterone series without androgenic properties. J Steroid Biochem. 1985 Aug;23(2):165-8. | |||||
| REF 18 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4778). | |||||
| REF 19 | Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry. 2021 Mar;8(3):191-201. | |||||
| REF 20 | Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia. J Pharmacol Exp Ther. 2022 Aug;382(2):223-232. | |||||
| REF 21 | Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov. 2013 Nov;12(11):866-85. | |||||
| REF 22 | The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial. J Clin Psychopharmacol. 2014 Apr;34(2):190-8. | |||||
| REF 23 | ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol. 2001 Dec;60(6):1414-20. | |||||
| REF 24 | Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1. ACS Med Chem Lett. 2010 October 14; 1(7): 350-354. | |||||
| REF 25 | Glycine Transport Inhibitors for the Treatment of Schizophrenia. Open Med Chem J. 2010; 4: 10-19. | |||||
| REF 26 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 935). | |||||
| REF 27 | Clinical pipeline report, company report or official report of GlaxoSmithKline (2009). | |||||
| REF 28 | A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies. Nucl Med Biol. 2008 Apr;35(3):315-25. | |||||
| REF 29 | [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1291-2. | |||||
| REF 30 | Pharmacological characterisation of the GlyT-1 glycine transporter using two novel radioligands. Neuropharmacology. 2010 Nov;59(6):558-65. | |||||
| REF 31 | The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci. 2003 Aug 20;23(20):7586-91. | |||||
| REF 32 | Structural insights into the inhibition of glycine reuptake. Nature. 2021 Mar;591(7851):677-681. | |||||
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