AAZ-A-154 targets 5-HT2 receptors (serotonin 2 receptors). It functions as a psychLight competitive antagonist and exhibits high selectivity for 5-HT2 receptors over dopamine, adrenergic, opioid, and other serotonin receptors. The compound shows negative ligand score (-31.7), indicating it is a non-hallucinogenic ligand of the 5-HT2AR. [1]
5-HT2A receptor (partial agonist, EC50 = 8.2 µM, efficacy = 17% span; Ki < 20 µM) [2][3]
5-HT2C receptor (activity observed; EC50 ~ 3.3 µM, Emax = 16%; Ki < 20 µM) [2][3]
5-HT2B receptor (full antagonist, no agonist activity; Ki < 20 µM) [2][3]
5-HT7 receptor (binding inhibition >50% at 10 µM; modest activity) [2][3]
Serotonin transporter (SERT) (Ki < 20 µM; low potency inhibitor) [2][3]
Sigma-1 receptor (Ki < 20 µM) [2][3]
5-HT1D receptor (modest activity) [3]
5-HT3 receptor (low potency inhibitor) [2][3]
Monoamine oxidase A (MAO-A) (low potency inhibitor) [2][3]
No detectable affinity for adrenergic or dopaminergic GPCRs, dopamine transporter (DAT), norepinephrine transporter (NET), or 5-HT1A receptors (EC50/IC50 > 30 µM). [2][3]

AAZ-A-154 (100 nM) promotes dendritic outgrowth in cultured rat embryonic cortical neurons, increasing dendritic arbor complexity to a comparable extent as ketamine. This psychoplastogenic effect is abolished by the 5-HT2R antagonist ketanserin (1 μM), suggesting that AAZ-A-154 triggers dendritic growth through activation of 5-HT2Rs. [1]
AAZ-A-154 exhibits high selectivity for 5-HT2 receptors as demonstrated using a panel of GPCR-based sensors (dopamine, adrenergic, opioid, and serotonin receptors) in both agonist and antagonist modes. [1]
Schild regression analysis reveals that AAZ-A-154 is a psychLight competitive antagonist. [1]

---

In Vitro: In cultured embryonic rat cortical neurons, Zalsupindole promoted neuritogenesis in a concentration-dependent manner. This effect was replicated by three independent laboratories (Olson Laboratory, Neurofit, Cellectricon). [2]
The neuritogenic effect of Zalsupindole was blocked by the 5-HT2 antagonist ketanserin and the mTOR inhibitor rapamycin, indicating 5-HT2-dependent mTOR pathway involvement. [2][3]
Zalsupindole did not activate the 5-HT2AR-based biosensor psychLight, failing to induce the conformational changes associated with hallucinogenic ligands. [2][3]
Zalsupindole did not increase cortical expression of c-Fos (immediate early gene) in the medial prefrontal or somatosensory cortex following systemic dosing, in contrast to psychedelic comparators. [3]
In radioligand binding assays (10 µM), Zalsupindole inhibited binding by >50% only at 5-HT7, 5-HT2B, and SERT. No significant inhibition was observed at adrenergic or dopaminergic GPCRs, ion channels, DAT, or NET. [2]
Functional assays confirmed Zalsupindole as a low potency (EC50 = 8.2 µM), low efficacy (span = 17%) partial agonist at 5-HT2A, and a full antagonist at 5-HT2B. [2][3]

AAZ-A-154 (20 mg/kg, i.p.) produces rapid (30 min) and long-lasting (1 week) antidepressant-like effects in the forced swim test (FST) in C57BL/6J mice. The compound decreased immobility in the FST, an effortful behavioral response commonly produced by other known psychoplastogens and antidepressants such as ketamine. [1]
In VMAT2 heterozygous (VMAT2-HET) mice (a model of depression), a single administration of AAZ-A-154 (15 mg/kg, i.p.) produced an anti-anhedonic effect, with treated VMAT2-HET mice exhibiting a sucrose preference indistinguishable from wild-type controls. This effect persisted for at least 12 days. The change in sucrose preference cannot be attributed to differential fluid consumption since both genotypes drank similar volumes of liquids across the entire experiment, and AAZ-A-154 did not modify sucrose preference in wild-type animals. [1]
AAZ-A-154 failed to produce any head-twitch responses (HTR), even at doses as high as 100 mg/kg (i.p.), confirming its non-hallucinogenic nature. However, a high dose of 100 mg/kg decreased locomotion in mice. [1]

---

In male rats, a single intraperitoneal (IP) dose of Zalsupindole (3, 10, 30 mg/kg) produced a dose-dependent increase in dendritic spine density in the medial prefrontal cortex (mPFC) 24 h post-administration, as measured by Golgi-Cox staining. Effects were comparable to ketamine (10 mg/kg) and psilocybin (3 mg/kg). The greatest effects were on mushroom and filopodia-like spines. [2]
In rat mPFC slices 24 h post-IP injection, Zalsupindole (10 mg/kg) significantly increased spontaneous excitatory postsynaptic current (sEPSC) frequency and amplitude, indicating enhanced functional plasticity. Effect sizes were greater than ketamine or psilocybin and comparable to DMT. [2]
In the rat forced swim test (FST), a single IP dose of Zalsupindole (10 mg/kg) produced a rapid (within 24 h) and sustained (at least 7 days) antidepressant-like effect, decreasing immobility similarly to ketamine (10 mg/kg). [2][3]
In VMAT2 heterozygous mice (depression model), a single dose of Zalsupindole alleviated anhedonia (increased sucrose preference) for >2 weeks. [2]
Zalsupindole did not induce head-twitch response (HTR) in mice at doses up to 30 mg/kg (IP), confirming lack of hallucinogenic potential. [2][3]
Microdialysis in rats showed that at 10 mg/kg (IP), Zalsupindole transiently (2 h) increased serotonin levels 2-fold but did not substantially alter norepinephrine, dopamine, acetylcholine, GABA, or glutamate. At 30 mg/kg, it increased serotonin (4-fold) and norepinephrine (2-fold). No glutamate burst was observed. [2][3]

Radioligand binding assays (CEREP): Zalsupindole was tested at 10 µM against a panel of 55 CNS targets. Percent inhibition of specific radioligand binding was calculated. Inhibition >50% was considered significant. [2]
5-HT2A and 5-HT2C radioligand binding: Competition binding was performed in 96-well plates containing binding buffer, membrane extracts, [³H]-DOI as radiotracer, and test compound. Non-specific binding was determined with 200-fold excess serotonin (5-HT). Samples were incubated at room temperature, filtered, washed, and counted using a MicroBeta counter. Ki values were calculated using the Cheng-Prusoff equation. [2]
IP-One HTRF assay (5-HT2A, 5-HT2C, 5-HT2B): CHO-K1 cells expressing human recombinant receptors were incubated with test compound or reference agonist (α-Me-5-HT) for 60 min at 37°C. After adding lysis buffer with IP1-d2 and anti-IP1 cryptate, fluorescence ratios were measured. For 5-HT2B, similar methods were used. [2]
MAO-A inhibition assay: Human MAO-A enzymatic LeadHunter assay was performed. [2]
SERT binding assay: Human SERT antagonist radioligand LeadHunter assay was performed. [2]
Sigma-1 receptor binding assay: Human sigma-1 agonist radioligand LeadHunter assay was performed. [2]
GTPγS assay (5-HT1D): HTRF-based assay was performed. [2]
cAMP assay (5-HT7): HTRF-based assay was performed. [2]
The primary characterization uses the psychLight biosensor and Schild regression analysis. [1]

Dendritogenesis assay in cultured cortical neurons: Timed-pregnant Sprague Dawley rats (E18) were used to obtain cortical neurons. Cultured neurons were treated with AAZ-A-154 (100 nM) or ketamine (1 μM, positive control). To assess the role of 5-HT2Rs, neurons were co-treated with the 5-HT2R antagonist ketanserin (1 μM). After treatment, neurons were fixed and stained, and dendritic arbor complexity was analyzed using Sholl analysis to determine the maximal number of crossings (Nmax). AAZ-A-154 increased Nmax comparable to ketamine, and this effect was blocked by ketanserin. [1]

---

Neurite outgrowth assay (Neurofit): Cortical neurons from E17 rat embryos were dissociated, seeded in 96-well plates (10,000 cells/well), and treated with Zalsupindole for 72 h. Cells were fixed with paraformaldehyde, permeabilized, blocked, and stained with anti-beta-III tubulin antibody followed by AF488 secondary antibody. Nuclei were stained with DAPI. Neurite networks were imaged and analyzed using high-content image analysis (CellInsight). Average neurite number and total neurite length per neuron were quantified. [2]
Neurite outgrowth and blocking assay (Cellectricon): Cortical neurons from E17.5 rat embryos were seeded in 384-well plates (2500 cells/well) and cultured for 72 h. Zalsupindole was added at six concentrations (1:3 dilutions, starting 10 µM) using an HP D300 digital dispenser. For blocking, ketanserin (100 µM) or rapamycin (100 µM) was added 1 h prior to Zalsupindole. On DIV9, cells were fixed, blocked, stained with Hoechst (nuclear) and anti-β-tubulin III (neurites). High-content imaging (Operetta) and analysis (Harmony software) were performed to quantify total neurite length. [2]

Forced Swim Test (FST) in C57BL/6J mice: Male and female C57BL/6J mice (9-10 weeks old, n=6 per sex per condition) were handled for 3 consecutive days prior to the first FST. Drug-naive mice underwent a pretest swim to induce a depressive-like phenotype. The next day, animals received intraperitoneal injections of AAZ-A-154 (20 mg/kg), ketamine (3 mg/kg, positive control), or vehicle (saline). After 30 minutes, mice underwent a 6-minute swim session in a clear Plexiglas cylinder filled with 30 cm of 24±1°C water. Immobility time (passive floating or remaining motionless with no activity other than keeping the head above water) was scored for the last 4 minutes of the 6-minute trial. One week later, the FST was repeated to assess sustained effects. All FSTs were performed between 0800 and 1300 h. [1]
Head-Twitch Response (HTR) and Locomotion Assays: Both male and female C57BL/6J mice (approximately 8 weeks old, 2 male and 2 female = 4 total per treatment) were used. Compounds were administered intraperitoneally (5 mL/kg) using 0.9% saline as vehicle. After injection, animals were placed into an empty cage, and HTRs were videotaped and scored later by two blinded observers. Locomotion was assessed using automated tracking software. AAZ-A-154 was tested at multiple doses (10, 30, 100 mg/kg) and failed to produce HTRs at any dose, though the 100 mg/kg dose decreased locomotion. [1]
Sucrose Preference Test in VMAT2-HET mice: Adult male and female wild-type (WT) and VMAT2 heterozygous (VMAT2-HET) mice were housed individually 48 hours prior to the experiment with ad libitum access to chow and water. Two hours prior to the beginning of the dark cycle, the home-cage water bottle was removed. One hour after onset of the dark cycle, a pair of bottles (water-water or water-sucrose) was placed into the home-cage. Mice were given 2 hours to drink, after which bottles were removed and weighed. This procedure was repeated daily with water-water pairing until the mouse showed stable drinking volumes over 3 consecutive days. Once criterion was achieved, mice were presented with water-sucrose pairing. The next day (day 1), mice were administered an acute injection of AAZ-A-154 (15 mg/kg, i.p.) and 5 minutes later were given the water-sucrose pairing. Subsequent water-sucrose pairings were presented on days 2 and 4, and then at 4-day intervals. Preference for the sucrose bottle was calculated as (volume of sucrose consumed minus volume of water consumed) divided by total volume of liquid consumed. [1]

---

Spinogenesis study: Male Sprague-Dawley rats (7 weeks old) received a single IP injection of Zalsupindole (3, 10, or 30 mg/kg), ketamine (10 mg/kg), psilocybin (3 mg/kg), or vehicle (0.9% saline) at 1 mL/kg. After 24 h, rats were euthanized, brains removed, and processed for Golgi-Cox staining (14-day impregnation, sectioned at 100-120 µm). Dendritic spine density on layer 5 pyramidal neurons in mPFC was quantified using Neurolucida software. [2]
Electrophysiology study: Male Sprague-Dawley rats (7-10 weeks) received IP injections of Zalsupindole (10 mg/kg), DMT (10 mg/kg), ketamine (10 mg/kg), psilocybin (1 mg/kg), or saline. After 24 h, rats were anesthetized and perfused with cold ACSF. Brain slices (300 µm) containing mPFC were prepared. Whole-cell patch-clamp recordings from layer 5 pyramidal neurons were performed at -70 mV to record sEPSCs. Data were acquired using MultiClamp 700B and analyzed with pClamp. [2]
Forced Swim Test (FST): Male Sprague-Dawley rats (7-9 weeks) received IP injections of Zalsupindole (10 mg/kg), ketamine (10 mg/kg), or saline after a 15-min pre-swim. The 5-min test swim was performed 24 h later and again on day 7. Behavior (immobility, climbing, swimming) was scored every 5 s. [2]
Head-Twitch Assay (HTR): Male C57BL/6J mice (5-6 weeks) received IP injections of psilocybin (1 mg/kg), DOI (1 mg/kg), or Zalsupindole (10 or 30 mg/kg). Immediately after treatment, mice were observed for 20 min, and HTR events (rapid side-to-side head shakes) were scored by blinded testers. [2]
Microdialysis: Male Sprague-Dawley rats (7-8 weeks) were implanted with I-shaped microdialysis probes in the PFC (AP +3.4 mm, L -0.8 mm, V -5.0 mm). After recovery, probes were perfused with aCSF at 1.5 µL/min. After basal collection, rats received IP Zalsupindole (3, 10, or 30 mg/kg). Dialysate was collected for 4 h. Neurotransmitter levels (DA, NE, 5-HT, Glu, GABA, ACh) were analyzed by HPLC-MS/MS. [2]

In rats, Zalsupindole administered IP (3, 10, 30 mg/kg) showed rapid and dose-proportionate distribution in plasma and brain. Half-life approximately 0.35 h, cleared rapidly following first-order kinetics. Brain-to-plasma ratio constant at ~10-25, indicating high brain penetration and low accumulation potential. [2][3]
Metabolism: Zalsupindole undergoes demethylation and oxidative primary metabolism followed by secondary/tertiary glucuronidation, hydroxylation, and sulfation. Three major metabolites (M1, M2, M3) were inactive in neurite outgrowth assays. [2][3]
In humans (Phase 1, oral dosing, 2-360 mg), Zalsupindole exhibited linear and predictable pharmacokinetics, dose-proportional absorption, and good CNS penetration. Food intake did not significantly alter absorption. [3]

In Phase 1 clinical trial (106 healthy volunteers, oral doses 2-360 mg), Zalsupindole was well tolerated with no dose-limiting toxicities, serious adverse events, or treatment-emergent hallucinations. No psychotomimetic symptoms, dissociation, or perceptual disturbances were reported. [3]
Cardiovascular safety: Zalsupindole is a full antagonist at 5-HT2B receptors (no agonism), indicating low potential for cardiac valvulopathy. No changes in heart rate, blood pressure, or ECG parameters were observed in Phase 1. [2][3]
No hepatotoxicity or other organ toxicity reported in preclinical or clinical studies. [2][3]

---

No specific toxicity data (such as LD50, hepatotoxicity, nephrotoxicity, or protein binding) are described for AAZ-A-154 in this paper. However, the compound failed to produce head-twitch responses at doses up to 100 mg/kg, indicating no hallucinogenic effects, though a high dose of 100 mg/kg decreased locomotion. The study notes that a full pharmacological profile including potential toxicity should be obtained in future work. [1]

[1]. Psychedelic-inspired drug discovery using an engineered biosensor. Cell. 2021 May 13;184(10):2779-2792.e18.

[2]. Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics. ACS Chem Neurosci. 2025 Nov 19;16(22):4388-4399.

[3]. Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics. ACS Chem Neurosci. 2026 Jan 21;17(2):382-391.

AAZ-A-154 (chemical name: (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine fumarate) is a non-hallucinogenic analog of a psychedelic compound. Its synthesis was described: to a solution of 5-methoxyindole in DMSO was added (R)-1-chloro-N,N-dimethylpropan-2-amine hydrochloride, potassium iodide, and potassium tert-butoxide. The reaction mixture was stirred for 24 hours, diluted with NaOH(aq), extracted with DCM, dried, filtered, and concentrated. The product was purified by flash chromatography, dissolved in CHCl3, and added dropwise to a boiling solution of fumaric acid in THF to yield the 1:1 fumarate salt (73% yield). The compound has a ligand score of -31.7 (negative, indicating non-hallucinogenic 5-HT2AR ligand). AAZ-A-154 shows high selectivity for 5-HT2 receptors. It produces rapid (30 min) and long-lasting (>2 week) beneficial behavioral effects in rodents following a single administration. Compared to tabernanthalog (TBG), another known non-hallucinogenic psychoplastogen, AAZ-A-154 appears more potent while producing more sustained antidepressant effects. The authors note that a full pharmacological profile including mechanism of action, off-target effects, pharmacokinetics, full dose-response studies, potential toxicity, and efficacy validated using other established assays should be obtained in future work. [1]

---

Zalsupindole is also known as DLX-001 and AAZ-A-154. It was discovered by the Olson Laboratory at UC Davis using the psychLight biosensor to screen for non-hallucinogenic 5-HT2A agonists. [2][3]
Mechanism: Promotes neuroplasticity via 5-HT2A-dependent mTOR signaling without Gq-mediated hallucinogenic signaling or glutamate burst. Low-efficacy partial agonism at 5-HT2A is hypothesized to underlie therapeutic effects without hallucinations. [2][3]
Indications: Being developed for major depressive disorder (MDD), with potential for PTSD, anxiety, substance use disorders, and neurodegenerative diseases. [2][3]
Clinical status: Phase 1 completed (safety, PK, EEG biomarkers). Phase 1b in MDD showed ~12-point MADRS reduction by Day 8, sustained to Day 36. FDA cleared Phase II design with at-home self-administration. [3]
Patent: Composition-of-matter patent US 11,254,640 B2 covers Zalsupindole and its salts through at least 2040. INN “Zalsupindole” assigned by WHO in 2023. [3]

C14H20N2O

232.32

232.15756326

C, 62.56; H, 7.88; Cl, 13.19; N, 10.42; O, 5.95

2481740-94-5

2481740-94-5; 2930845-96-6 (HBr); 2930845-92-2 (benzoate); 2930845-89-7 (HCl); 2481740-95-6 (fumarate); 2930845-94-4; 2930846-03-8 (mesylate); 2481741-75-5 (S-isomer free base)

154694212

Light yellow to yellow viscous liquid

2.4

0

2

4

17

244

1

C[C@H](CN1C=CC2=C1C=CC(=C2)OC)N(C)C

KHEUWLQKCXGVEL-LLVKDONJSA-N

InChI=1S/C14H20N2O/c1-11(15(2)3)10-16-8-7-12-9-13(17-4)5-6-14(12)16/h5-9,11H,10H2,1-4H3/t11-/m1/s1

(2R)-1-(5-methoxyindol-1-yl)-N,N-dimethylpropan-2-amine

Zalsupindole; AAZ-A-154; DTXSID901336869; AAZA154; AAZ-A-154 HCl; AAZA-154 HCl; RefChem:1075133; DTXCID001767164; AAZ-A 154; AAZ-A154; AAZA 154; DLX-001 HCl; DLX 001 HCl; DLX001 HCl; 2481740-94-5;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Soluble in DMSO (>10 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)