The drug is a highly potentfull agonist of the human TAAR1 with an EC50Tooltip half-maximal effective concentration of 4.0nM and an EmaxTooltip half-maximal effective concentration 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 antagonistdizocilpine (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]
1234Cano-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. PMID39874393. 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]. [...]
123456Krasavin M, Lukin A, Sukhanov I, Gerasimov AS, Kuvarzin S, Efimova EV, etal. (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. PMC9687812. PMID36359001. 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.
1234Dorofeikova 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.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as the List of trace amines, TAAR, and TAAR1 pages. See also:Receptor/signaling modulators
