LK00764
LK00764 is a trace amine-associated receptor 1 (TAAR1) agonist that is being investigated for the treatment of schizophrenia and other psychiatric disorders. The drug is a highly potent full agonist of the human TAAR1 with an EC50Tooltip half-maximal effective concentration of 4.0 nM and an EmaxTooltip half-maximal effective concentration of 101%. It is 30-fold more potent as a TAAR1 agonist than ulotaront (SEP-363856) in vitro. The drug has been found to reverse the hyperlocomotion in dopamine transporter (DAT) knockout mice and the hyperactivity induced by the NMDA receptor antagonist dizocilpine (MK-801) in rats, which are considered to be antipsychotic-like effects. It also attenuates stress-induced hyperthermia in rats, which is thought to be an anxiolytic-like effect. Hence, LK00764 appears to not only be an agonist of the human TAAR1, but also of the mouse and rat TAAR1, although this does not seem to have been assessed in vitro. LK00764 was first described in the scientific literature by 2018. It is being developed by Accellena. As of February 2025, the drug is in the preclinical research stage of development. LK00764 is structurally distinct from other known TAAR1 agonists but contains β-phenethylamine-like structural features.
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| Drug class | Trace amine-associated receptor 1 (TAAR1) agonist |
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| Formula | C16H15ClN4 |
| Molar mass | 298.77 g·mol−1 |
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LK00764 is a trace amine-associated receptor 1 (TAAR1) agonist that is being investigated for the treatment of schizophrenia and other psychiatric disorders.[1][2][3][4]
The drug is a highly potent full agonist of the human TAAR1 with an EC50 of 4.0 nM and an Emax of 101%.[3] It is 30-fold more potent as a TAAR1 agonist than ulotaront (SEP-363856) in vitro.[3] The drug has been found to reverse the hyperlocomotion in dopamine transporter (DAT) knockout mice and the hyperactivity induced by the NMDA receptor antagonist dizocilpine (MK-801) in rats, which are considered to be antipsychotic-like effects.[2][4] It also attenuates stress-induced hyperthermia in rats, which is thought to be an anxiolytic-like effect.[3] Hence, LK00764 appears to not only be an agonist of the human TAAR1, but also of the mouse and rat TAAR1, although this does not seem to have been assessed in vitro.[2][3][4]
LK00764 was first described in the scientific literature by 2018.[4] It is being developed by Accellena.[1] As of February 2025, the drug is in the preclinical research stage of development.[1] LK00764 is structurally distinct from other known TAAR1 agonists but contains β-phenethylamine-like structural features.[2][3]
References
[edit]- ^ a b c "Delving into the Latest Updates on LK00764 with Synapse". Synapse. 23 January 2025. Retrieved 7 February 2025.
- ^ a b c d Cano-Ramírez H, Hoffman KL (January 2025). "The role of rodent behavioral models of schizophrenia in the ongoing search for novel antipsychotics". Expert Opinion on Drug Discovery. 20 (2): 217–231. doi:10.1080/17460441.2025.2459807. PMID 39874393.
This same laboratory discovered yet another TAAR1 agonist (LK00764), also chemically distinct from those currently known. LK00764 was shown to reduce hyperlocomotion in DAT knockout rats, as well as reduce MK-801-induce hyperactivity and spontaneous activity in rats [Citation94]. [...]
- ^ a b c d e f Krasavin M, Lukin A, Sukhanov I, Gerasimov AS, Kuvarzin S, Efimova EV, et al. (November 2022). "Discovery of Trace Amine Associated Receptor 1 (TAAR1) Agonist 2-(5-(4'-Chloro-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders". Biomolecules. 12 (11). doi:10.3390/biom12111650. PMC 9687812. PMID 36359001.
The rigidified biphenyl analogs 58—67 appeared to display a much better, full agonistic profile with respect to TAARI. Clearly, the linear p-biphenyl versions 58—65 were preferred over m-biphenyl counterparts 66—67. Simply based on the best potency displayed by compound 62 (LK00764) (its potency (EC5() 4 nM) being more than 30 times higher than that of Ulotaront (EC50 140 nM) [31], which received FDA Breakthrough Therapy Designation and is currently being investigated in Phase 3 clinical trials [9], it was nominated for further evaluation in rodent pharmacological tests sensitive to TAARI agonists [ and relevant to the development of novel antipsychotics.
- ^ a b c d Dorofeikova M, Gerasimov A, Lukin A, Sukhanov I, Krasavin M, Gainetdinov RR (2019). "Identification of a novel trace amine-associated receptor 1 agonist with in vivo activity". European Neuropsychopharmacology. 29: S190. doi:10.1016/j.euroneuro.2018.11.320.