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

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-phenylethylamine or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

The mixture was heated at reflux under argon for 3-4 h while the progress of the reaction was monitored by thin-layer chromatography (eluent-2% methanol in chloroform). On completion, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with 5% aq. K 2 CO 3 , passed through a plug of anhydrous Na 2 SO 4 , and concentrated in vacuo and the residue was treated, fractionated, on silica gel using 50% ethyl acetate in hexane as eluent. Fractions containing the coupling product were pooled and concentrated to dryness. The residue was treated with 4M solution of HCl in 1,4-dioxane (1 h, room temperature). Following concentration on a rotary evaporator, the crystalline residue was triturated with ether and the solids were filtered off, washed with more ether, and air-tried to provide an analytically pure title compound as a crystalline residue.   13

In Silico Modeling
The TAAR1 protein homology model was built with AlphaFold software [17]. The protein model (Q96RJ0) was downloaded from the Uniprot database [18]. The downloaded protein model was preprocessed with the use of a protein preparation wizard, included in Schrodinger Suite (version 2021-4). At this step, we eliminate typical errors in the protein model, such as invalid bond orders, protonation states, atom typing, missing amino acid sidechains, missing loops, clashes between sidechains, incorrect torsions, etc. All manipulations with proteins and ligands were carried out in the OPLS46 force field, used in Schrodinger Suite [19]. The three-dimensional structure of the ligands used for calculations was generated in the same forcefield-OPLS46 [19]. Moreover, for all ligands, possible protonation states were calculated with the use of the Epik module of Schrodinger Suite [20]. Ligand docking with the prepared TAAR1 protein model was performed with the use of a Glide induced-fit docking (IFD) method [21]. This takes into account protein flexibility in the presence of ligand. The IFD protocol supports direct grid box placement. The grid box for molecular docking was centered on the following TAAR1 residues: D103, I104, S107, V184, F186, T194, F195, F267, F268, I290, and Y294. The grid size is: 16 × 16 × 16 Å. Protein structure refinement during IFD was limited by 6Å of ligand poses with sidechain optimization. The first docking step generated 20 poses per ligand. For redocking (after protein structure refinement), structures within 30 kcal/mol of the best structure and within the top 15 structures per ligand were selected. The best-fitting binding pose was selected in accordance with docking solutions clustering and interactions with the crucial residues found in literature [9,16,22]. Final prioritization was determined by IFDscore and GlideScore values. The metadynamics calculations protocol was fully automatic: solvent-SPC, automatic counterions addition, system size in accordance to the protein-ligand complex with buffer zone of 10 Å. Equilibration: GCMC Solvate Pocket, muVT ensemble, T = 300 K, restraints on heavy atoms; GCMC Solvate Pocket, muVT ensemble, T = 300 K, no restraints; Brownian Dynamics NVT, T = 300 K, small timesteps, and restraints on solute heavy atoms. Main simulation-10 ns, NPT, T = 300 K. For each ligand, metadynamics simulation was repeated seven times, which was necessary for statistical weighting. On the basis of molecular metadynamics calculations, the protein-ligand complex stability was evaluated by RMSD value calculation for a ligand near protein. The second value-persistence CompScore, value including protein-ligand interactions, such as π-π stacking, hydrogen bonds, and salt bridges.

BRET Analysis
The Bioluminescence Resonance Energy Transfer approach (BRET) has been used for functional activity experiments. HEK-293 cells were transiently transfected with cDNA for TAARs and cAMP BRET biosensor (EPAC) and then plated in a 96-well plate, as described [23]. All compounds were tested at the initial concentration of 10 µM. Then, for active compounds, a concentration-response analysis was performed in order to calculate the EC 50 values. A natural agonist of TAAR1 β-phenylethylamine (β-PEA) was used as a positive control.
2.6. In Vivo Efficacy Evaluation 2.6.1. Subjects Drug and test naïve Wistar (3-4 months old in the beginning of experiments) rats were purchased from the State Breeding Farm "Rappolovo" (St. Petersburg, Russia). The recently described dopamine transporter knockout rats (DAT-KOs) were raised in an animal facility of the Valdman Institute of Pharmacology. All rodents were housed under standard laboratory conditions: 12 h light/dark cycle (lights on at 08:00 h) at 21 ± 2 • C and 50 ± 20% humidity. The rats were housed in groups of three to five in standard T IV cages (Tecniplast, Buguggiate, VA, Italy). During the entire experiment, the rats had free access to filtered ("AQUAPHOR", Saint Petersburg, Russia) tap water and standard laboratory rat chow (receipt ΠK 120-1, KKZ "Laboratorkorm", Moscow, Russia). All experiments were carried out during the light period of the light/dark cycle after at least one week of habituation to the animal facility. The cages, corn cob bedding ("KKZ "Zolotoy pochatok"" LLC, Voronezh, Russia), and water bottles were changed once a week.
Experimental protocols were approved by the Local Animal Care and Use Committee of First Pavlov State Saint Petersburg Medical University.

Compounds
MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10imine maleate; Sigma-Aldrich, St. Louis, MO, USA) was dissolved in saline. Compound 62 (LK00764) was dissolved in 10% Tween 80 saline solution. All solutions were made fresh shortly before injections. Drug doses were tested in a pseudo-random order derived from Latin square design with at least 72 h between consecutive tests. All drugs and vehicles were administered intraperitoneally (i.p.) in the volume of 1 mL/kg. Drug doses are reported as salts. Selection of the MK-801 dose (0.2 mg/kg) was based the previous experience with the compound [24]. All locomotor activity tests (duration-60 min) were performed 15 min after the administration of compounds.

Evaluation of Rat Locomotor Activity Following Drug i.p. Administration
We evaluated locomotor activity of rats in the Actometer apparatus. A detailed description of the apparatus has been presented before [25]. Shortly, each box of the apparatus was equipped by photocell-based infrared sensors to assess horizontal and vertical activity. Wistar rats were tested in the apparatus following a one-week habituation period (baseline period). During this period, the animals were placed in locomotor activity boxes for 60 min per day, 6 days a week to habituate them to the environment. The pharmacological challenge in DAT-KO rats was conducted without habituation to the apparatus.

Stress-Induced Hyperthermia (SIH)Test
SIH test is commonly used to evaluate the potential anti-anxiety effect of drugs [26]. Thermometry was performed rectally in rats with a BIOSEB thermometer. Eight Wistar male rats were injected i.p. with vehicle or LK00764, dissolved in 10% tween 80 saline solution. Latin square design was used for the experiment. The first measurement was performed directly before the injection and the second measurement was performed 15 min later. The difference between the first and the second temperature was calculated.

Statistical Analysis
We used nonparametric statistical methods to analyze the data of the locomotor experiments [25,26]. Alpha was set at 0.05. All statistical analyses were performed using SigmaPlot 12.5 (Systat Software Inc., San Jose, CA, USA). For analysis of the SIH test experiments, Kruskal-Wallis one-way ANOVA was applied.

Chemistry
In order to identify new compounds which do not belong to the chemotypes depicted in Figure 1, we performed screening of a focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to β-PEA or tyramine, well established ligands of TAAR1, as well as other biogenic amine GPCRs. Such a strategy had been reported to deliver higher hit rates in screening a corporate compound collection containing compounds from historic biogenic amine-based drug discovery programs [15]. This hit finding effort identified two submicromolar agonists of TAAR1 (1 and 2), both of which displayed a dose-dependent activation of the receptor and were based on the same 2-(4H-1,2,4-triazol-3-yl)ethan-1-amine core not previously associated with TAAR1 modulation in the literature (Figure 2).
In order to improve the potency of the newly identified chemotype and possibly understand structure-activity relationships, we performed a massive hit-to-lead analog synthesis by utilizing diversely substituted stock-available (hetero)aromatic carboxylic acid hydrazides 3 and Boc-protected amino amidine building block 4 [27], as depicted in Scheme 1. The three steps were conducted with only one intermittent chromatographic purification after the neat melting of N-acyl amidrazone 5. Thus, the yields of hydrochlorides 6-57 were calculated over the three consecutive steps.

TAAR1 Agonistic Activity
Hit expansion compounds 6-57 and 58-67 (see Supplementary Materials for characterization data) were tested for TAAR1 activation using the earlier-developed BRET assay [30]. In addition to EC50 values obtained for each compound, its maximum agonistic effect (Emax) was compared to that produced by 1 μM β-phenylethylamine (β-PEA) TAAR1 agonist, employed in this assay as a reference [31]. The data obtained for the initial set of analogs are compiled in Table 1.

TAAR1 Agonistic Activity
Hit expansion compounds 6-57 and 58-67 (see Supplementary Materials for characterization data) were tested for TAAR1 activation using the earlier-developed BRET assay [29]. In addition to EC 50 values obtained for each compound, its maximum agonistic effect (E max ) was compared to that produced by 1 µM β-phenylethylamine (β-PEA) TAAR1 agonist, employed in this assay as a reference [30]. The data obtained for the initial set of analogs are compiled in Table 1. Table 1. Agonistic activity of 2-(4H-1,2,4-triazol-3-yl)ethan-1-amine analogs 6-57 of screening hit compounds 1-2 with respect to TAAR1 receptor a .

TAAR1 Agonistic Activity
Hit expansion compounds 6-57 and 58-67 (see Supplementary Materials for characterization data) were tested for TAAR1 activation using the earlier-developed BRET assay [30]. In addition to EC50 values obtained for each compound, its maximum agonistic effect (Emax) was compared to that produced by 1 μM β-phenylethylamine (β-PEA) TAAR1 agonist, employed in this assay as a reference [31]. The data obtained for the initial set of analogs are compiled in Table 1.

TAAR1 Agonistic Activity
Hit expansion compounds 6-57 and 58-67 (see Supplementary Materials for characterization data) were tested for TAAR1 activation using the earlier-developed BRET assay [30]. In addition to EC50 values obtained for each compound, its maximum agonistic effect (Emax) was compared to that produced by 1 μM β-phenylethylamine (β-PEA) TAAR1 agonist, employed in this assay as a reference [31]. The data obtained for the initial set of analogs are compiled in Table 1. Table 1. Agonistic activity of 2-(4H-1,2,4-triazol-3-yl)ethan-1-amine analogs 6-57 of screening hit compounds 1-2 with respect to TAAR1 receptor. a. From the examination of the activity data obtained for the unbiased SAR survey set (6-57), it becomes apparent that a simple variation in substituents on the aromatic ring does not lead to substantial improvement in potency. Most of the active compounds manifested themselves as full TAAR1 agonists. Among other things, this initial SAR survey revealed that replacement of the aryl moiety with thienyl (cf. 16 and 18) or nitrogen heteroaromatic (cf. 10, 35 and 38) as well as highly electron-rich moieties (cf. 11, 24, 30, 32) was detrimental to the potency. At the same time, substitution of the benzene ring with lipophilic groups in the para-position appears to have a positive effect on the agonistic activity ( cf. 19, 40, 43-45), which reaches into the double-digit nanomolar range. Interestingly, the position of the 'walking fluorine' in two groups of analogs-43-45 and 46-48has little effect on the potency. However, methyl substitution in the proximal benzene ring (in 46-48) led to a noticeable drop in the activity. A similar lowering of the activity results from the introduction of iodo substitutions in the phenyl ring (cf. 41-42 and 56). Introduction of a hydroxy substituent in the phenyl ring (cf. 55 and 57) completely ablates the ag-

>1000
a Mean from 3 different BRET assays (errors were in the range of ±5-10% of the reported values). b Maximum observed activation of TAAR1 relative to that observed for 1 µM of β-PEA.
From the examination of the activity data obtained for the unbiased SAR survey set (6-57), it becomes apparent that a simple variation in substituents on the aromatic ring does not lead to substantial improvement in potency. Most of the active compounds manifested themselves as full TAAR1 agonists. Among other things, this initial SAR survey revealed that replacement of the aryl moiety with thienyl (cf. 16 and 18) or nitrogen heteroaromatic (cf. 10, 35 and 38) as well as highly electron-rich moieties (cf. 11, 24, 30, 32) was detrimental to the potency. At the same time, substitution of the benzene ring with lipophilic groups in the para-position appears to have a positive effect on the agonistic activity (cf. 19, 40, 43-45), which reaches into the double-digit nanomolar range.
Interestingly, the position of the 'walking fluorine' in two groups of analogs-43-45 and 46-48-has little effect on the potency. However, methyl substitution in the proximal benzene ring (in 46-48) led to a noticeable drop in the activity. A similar lowering of the activity results from the introduction of iodo substitutions in the phenyl ring (cf. 41-42 and 56). Introduction of a hydroxy substituent in the phenyl ring (cf. 55 and 57) completely ablates the agonistic activity.
As hinted at in Section 3.1. Chemistry, above, the latter observation inspired us to explore the rigidified biphenyl versions of the initial hits 58-67, which were also tested against TAAR1 in BRET assay. The EC 50 values obtained for this subset of analogs are compiled in Table 2.   The rigidified biphenyl analogs 58-67 appeared to display a much better, full agonistic profile with respect to TAAR1. Clearly, the linear p-biphenyl versions 58-65 were preferred over m-biphenyl counterparts 66-67. Simply based on the best potency displayed The rigidified biphenyl analogs 58-67 appeared to display a much better, full agonistic profile with respect to TAAR1. 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 (EC 50 4 nM) being more than 30 times higher than that of Ulotaront (EC 50 140 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 TAAR1 agonists [6,7,10,11] and relevant to the development of novel antipsychotics.

In Silico Modeling
No crystal structure of TAAR1 is available in the Protein Data Bank (PDB). However, modelled structures of TAAR1-interactions obtained by homology modeling can be found in GproteinDb [32]. For instance, a homology model for TAAR1 has been built [9,33] based on the structure of the β2-adrenergic receptor [34] and used in virtual screening of new TAAR1 ligands [35]. Induced-fit docking of 62 (LK000764) showed a high affinity level of this ligand to TAAR1, which was confirmed by the calculated scoring function values: GScore (kcal/mol): −10.77; IFDScore(kcal/mol): −648.38. The analysis of the binding pose revealed that 62, in its complex with TAAR1, forms a rich network of lipophilic proteinligand contacts. The strongest lipophilic contacts were registered in the phenylalanine-rich region of TAAR1: Phe185/186 and Phe195/267/268. This fact was confirmed by the high calculated increment of lipophilic contacts in the scoring function value: −4.27 kcal/mol. The biphenyl moiety of 62 contributes most to these interactions, which is further supported by the π-π stacking interaction with the Phe267 aromatic ring. The other key interaction defining the binding pose is the salt bridge between Asp274 and the protonated amine moiety of 62, possibly supported by hydrogen bonding to the same Asp274 residue and to the Ile281 backbone residue (Figure 3).
The protein-ligand complex of 62 (LK000764) was tested with the molecular metadynamics method in order to assess molecule retention stability in the TAAR1 active site [36]. The purpose of this method is to evaluate the stability of poses with a Desmond metadynamics [37] molecular dynamics simulation to determine the correctness of the docking pose. The stability was assessed in terms of the fluctuations of the ligand RMSD over the course of the simulation and the persistence of important contacts between the ligand and the receptor (and any other cofactors or solvent molecules) such as hydrogen bonds and π-π interactions. The collective variable for the metadynamics simulation is the ligand RMSD from its initial pose, evaluated after superposition of the binding sites to account for drift. To improve the statistics, multiple simulations were performed, and the results were averaged over the simulations.
high calculated increment of lipophilic contacts in the scoring function value: −4.27 kcal/mol. The biphenyl moiety of 62 contributes most to these interactions, which is further supported by the π-π stacking interaction with the Phe267 aromatic ring. The other key interaction defining the binding pose is the salt bridge between Asp274 and the protonated amine moiety of 62, possibly supported by hydrogen bonding to the same Asp274 residue and to the Ile281 backbone residue (Figure 3 The protein-ligand complex of 62 (LK000764) was tested with the molecular metadynamics method in order to assess molecule retention stability in the TAAR1 active site [37]. The purpose of this method is to evaluate the stability of poses with a Desmond metadynamics [38] molecular dynamics simulation to determine the correctness of the docking pose. The stability was assessed in terms of the fluctuations of the ligand RMSD

Effect on MK-801-Induced Hyperactivity and Spontaneous Activity in Rats
Glutamate NMDA receptor antagonist-induced hyperactivity in rodents is commonly used as a pharmacological animal model of schizophrenia in the screening of potential antipsychotics. It is known that the pharmacological activation of TAAR1 is able to decrease NMDA blockers-induced hyperactivity in rodents [8,38]. Thus, we used MK-801 (0.2 mg/kg, i.p.) treatment to induce hyperactivity in rats and analyzed the effects of compound 62 (LK00764) at doses of 0.3, 1, 3, 5, and 10 mg/kg, i.p. on locomotor activity of MK-801-treated Wistar rats.
Next, we analyzed the locomotor effects of compound 62 (LK00764, 0.3-10 mg/kg, i.p.) on the additional group of intact rats (n = 9). The administration of compound 62 (LK00764) did not affect horizontal but decreased vertical activity of untreated rats ( Figure 5A,B). The Friedmann test demonstrated that the pretreatment with compound 62 (LK00764) did not affect the horizontal activity of Wistar rats (the main effect of the factor 'dose': χ 2 = 3.63, df = 5, p = 0.60) but diminished vertical activity of the animals (the main effect of the factor 'dose': χ 2 = 27.11, df = 5, p < 0.001). Next, we analyzed the locomotor effects of compound 62 (LK00764, 0.3-10 mg/kg, i.p.) on the additional group of intact rats (n = 9). The administration of compound 62 (LK00764) did not affect horizontal but decreased vertical activity of untreated rats ( Figure  5A,B). The Friedmann test demonstrated that the pretreatment with compound 62 (LK00764) did not affect the horizontal activity of Wistar rats (the main effect of the factor 'dose': χ2 = 3.63, df = 5, p = 0.60) but diminished vertical activity of the animals (the main effect of the factor 'dose': χ2 = 27.11, df = 5, p < 0.001).

Effects on Spontaneous Locomotor Hyperactivity of Dopamine Transporter Knockout (DAT-KO) Rats
Animals without DAT have a disrupted re-uptake of dopamine resulting in remarkably elevated extracellular dopamine levels and spontaneous locomotor hyperactivity [40]. Hyperdopaminergic DAT-KO mice and rats are routinely used in search of potential antipsychotic drugs [40,41]. As has been demonstrated in previous studies, TAAR1 agonists are able to mitigate locomotor hyperactivity induced by the lack of DAT [10,39,40]. Thus, we next evaluated the effects of LK00764 (1-10 mg/kg, i.p.) on spontaneous locomotor hyperactivity of DAT-KO rats (n = 9).
We found that the administration of compound 62 (LK00764) was accompanied by a significant dose-dependent decrease in both horizontal (the main effect of the factor 'dose': χ2 = 9.69, df = 4, p < 0.05) and vertical (the main effect of the factor 'dose': χ2 = 9.69, df = 4, p < 0.05) activity. The Dunnett's test revealed that only the highest tested dose, 10 mg/kg, significantly (p < 0.05) diminished locomotor hyperactivity of the mutants ( Figure  6A,B).

Effects on Spontaneous Locomotor Hyperactivity of Dopamine Transporter Knockout (DAT-KO) Rats
Animals without DAT have a disrupted re-uptake of dopamine resulting in remarkably elevated extracellular dopamine levels and spontaneous locomotor hyperactivity [39]. Hyperdopaminergic DAT-KO mice and rats are routinely used in search of potential antipsychotic drugs [39,40]. As has been demonstrated in previous studies, TAAR1 agonists are able to mitigate locomotor hyperactivity induced by the lack of DAT [10,38,39]. Thus, we next evaluated the effects of LK00764 (1-10 mg/kg, i.p.) on spontaneous locomotor hyperactivity of DAT-KO rats (n = 9).
We found that the administration of compound 62 (LK00764) was accompanied by a significant dose-dependent decrease in both horizontal (the main effect of the factor 'dose': χ 2 = 9.69, df = 4, p < 0.05) and vertical (the main effect of the factor 'dose': χ 2 = 9.69, df = 4, p < 0.05) activity. The Dunnett's test revealed that only the highest tested dose, 10 mg/kg, significantly (p < 0.05) diminished locomotor hyperactivity of the mutants ( Figure 6A,B).
We found that the administration of compound 62 (LK00764) was accompanied by a significant dose-dependent decrease in both horizontal (the main effect of the factor 'dose': χ2 = 9.69, df = 4, p < 0.05) and vertical (the main effect of the factor 'dose': χ2 = 9.69, df = 4, p < 0.05) activity. The Dunnett's test revealed that only the highest tested dose, 10 mg/kg, significantly (p < 0.05) diminished locomotor hyperactivity of the mutants ( Figure  6A,B).

Effects on Stress-Induced Hyperthermia in Rats
Another behavioral paradigm known to be affected by TAAR1 agonists is the stressinduced hyperthermia test, which is believed to be a sensitive approach to evaluate the anxiolytic action of compounds [10, 42, 39a]. Thus, compound 62 (LK00764) was evaluated in this test at doses of 3 and 5 mg/kg, i.p. (Figure 7). At both doses, this compound was effective in suppressing stress-induced hyperthermia in rats (p < 0.05 and p < 0.001 for 3 and 5 mg/kg, respectively; Dunn's test).

Effects on Stress-Induced Hyperthermia in Rats
Another behavioral paradigm known to be affected by TAAR1 agonists is the stressinduced hyperthermia test, which is believed to be a sensitive approach to evaluate the anxiolytic action of compounds [10, 42, 39a]. Thus, compound 62 (LK00764) was evaluated in this test at doses of 3 and 5 mg/kg, i.p. (Figure 7). At both doses, this compound was effective in suppressing stress-induced hyperthermia in rats (p < 0.05 and p < 0.001 for 3 and 5 mg/kg, respectively; Dunn's test).

Conclusions
TAAR1 agonism is emerging as a principally new treatment option for a number of mental conditions, including schizophrenia [7]. Particularly intriguing is the recently demonstrated ability of the TAAR1 agonist Ulotaront to exert potent antipsychotic activity without blocking D2 dopamine receptors, thereby avoiding common side-effects of D2 dopamine receptor antagonists [8,9]. Here, we have reported the identification of the novel potent TAAR1 agonist compound 62 (LK00764) with pronounced in vivo activity.
Compound 62 (LK00764) demonstrated efficacy in rats through the use of four behavioral tests typically employed in the screening of antipsychotic drugs and known to demonstrate a response to TAAR1 agonists. Further preclinical studies, including the comparison of the pharmacodynamic effects of compound 62 to those of the most advanced TAAR1 agonists as well as classical antipsychotics, are necessary to evaluate the efficacy, safety,

Conclusions
TAAR1 agonism is emerging as a principally new treatment option for a number of mental conditions, including schizophrenia [7]. Particularly intriguing is the recently demonstrated ability of the TAAR1 agonist Ulotaront to exert potent antipsychotic activity without blocking D 2 dopamine receptors, thereby avoiding common side-effects of D 2 dopamine receptor antagonists [8,9]. Here, we have reported the identification of the novel potent TAAR1 agonist compound 62 (LK00764) with pronounced in vivo activity.
Compound 62 (LK00764) demonstrated efficacy in rats through the use of four behavioral tests typically employed in the screening of antipsychotic drugs and known to demonstrate a response to TAAR1 agonists. Further preclinical studies, including the comparison of the pharmacodynamic effects of compound 62 to those of the most advanced TAAR1 agonists as well as classical antipsychotics, are necessary to evaluate the efficacy, safety, and tolerability of this potent and efficacious TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.