| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
The primary molecular target of zalsupindole is the serotonin 5-HT2A receptor, where it functions as a biased agonist. This biased agonism is crucial to its mechanism—it activates specific downstream signaling pathways (including Gq-mediated signaling) while avoiding those pathways responsible for hallucinogenic effects, such as β-arrestin recruitment and the induction of the head-twitch response. Notably, the compound demonstrates no measurable agonism at the 5-HT2B receptor, a target linked to cardiac valvulopathy, thereby mitigating a significant safety concern associated with some serotonergic drugs.
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| ln Vitro |
In laboratory studies, zalsupindole promotes neuritogenesis (the growth of neuronal processes) and increases dendritic spine density in cortical neurons. These neuroplastic effects are dependent on the 5-HT2A receptor, as they can be completely blocked by ketanserin, a selective 5-HT2 antagonist. Furthermore, studies utilizing rapamycin (an mTOR inhibitor) suggest that the neuroplastic effects of zalsupindole involve the mTOR signaling pathway, a key mechanism for protein synthesis and synaptic growth. Critically, unlike classical psychedelics such as psilocybin or LSD, it does not induce cellular characteristics of hallucinogenic compounds, and its effects on structural plasticity are comparable to or greater than those of ketamine, psilocybin, and DMT.
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| ln Vivo |
In rodent models, zalsupindole produces rapid and sustained antidepressant-like effects following a single dose, as evidenced by efficacy in the forced swim test (FST) and VMAT2-deficient mouse models. Its effects on structural neuroplasticity in the prefrontal cortex are comparable to or greater than those of ketamine, psilocybin, and DMT. Most importantly, despite its 5-HT2A activity, zalsupindole does not induce the head-twitch response (HTR) in rodents, which is the primary behavioral proxy for hallucinations in humans, confirming its non-hallucinogenic and non-dissociative profile. In Phase Ib clinical trials in MDD patients, a single week of treatment produced approximately 50% reduction in MADRS scores (12-point improvement) by Day 8, with durability maintained through Day 36.
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| Enzyme Assay |
The standard methodology for characterizing zalsupindole's receptor binding involves radioligand binding assays using membrane preparations from cells expressing human recombinant serotonin receptors (including 5-HT2A, 5-HT2B, and 5-HT2C). In these cell-free systems, increasing concentrations of zalsupindole compete with a high-affinity radioligand (such as [³H]-ketanserin for 5-HT2A) to determine its binding affinity (Ki value). Functional bias is subsequently assessed using non-radioactive methods like IP-1 accumulation (measuring Gq pathway activation) or β-arrestin recruitment assays to differentiate between signaling pathways, which is essential for confirming its biased agonist profile.
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| Cell Assay |
The standard methodology for characterizing zalsupindole's receptor binding involves radioligand binding assays using membrane preparations from cells expressing human recombinant serotonin receptors (including 5-HT2A, 5-HT2B, and 5-HT2C). In these cell-free systems, increasing concentrations of zalsupindole compete with a high-affinity radioligand (such as [³H]-ketanserin for 5-HT2A) to determine its binding affinity (Ki value). Functional bias is subsequently assessed using non-radioactive methods like IP-1 accumulation (measuring Gq pathway activation) or β-arrestin recruitment assays to differentiate between signaling pathways, which is essential for confirming its biased agonist profile.
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| Animal Protocol |
The primary rodent model used to confirm non-hallucinogenic activity is the Head-Twitch Response (HTR) assay. A typical protocol involves administering zalsupindole (or vehicle/positive control like DOI or psilocybin) to male C57BL/6J mice via oral gavage or intraperitoneal injection. The number of head twitches is then counted by a blinded observer for a specific period (e.g., 20-60 minutes post-injection). Additionally, the Forced Swim Test (FST) is used to assess antidepressant-like effects; rodents are placed in a water-filled cylinder, and immobility time is measured 24 hours after zalsupindole administration to assess rapid onset of action. VMAT2-deficient mouse models have also been used to demonstrate efficacy.
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| ADME/Pharmacokinetics |
In rat studies, zalsupindole demonstrates rapid brain penetration after systemic administration, suggesting good blood-brain barrier permeability. In Phase 1 human clinical trials, the drug exhibits linear pharmacokinetics with dose-proportional absorption across a wide range (2 mg to 360 mg). It shows high central nervous system (CNS) penetration, and its absorption profile supports oral dosing, with the benzoate salt formulation designed to optimize these properties. Electroencephalogram (EEG) biomarkers in humans showed dose-dependent increases in power spectra associated with synaptic potentiation, confirming target engagement in the brain. Phase Ib data also demonstrated robust translational biomarkers including quantitative EEG (qEEG) and polysomnography (PSG) findings.
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| Toxicity/Toxicokinetics |
Preclinical safety assessments highlight a favorable safety profile. Zalsupindole lacks measurable agonism at the 5-HT2B receptor, mitigating the risk of drug-induced valvular heart disease associated with some serotonergic drugs. In Phase 1 clinical trials across over 120 participants to date, oral zalsupindole was reported to be well-tolerated across a dose range of 2–360 mg. There were no reports of psychotomimetic effects (hallucinations or dissociation), no serious adverse events, and all adverse events were mild and resolved without intervention. The favorable safety profile has enabled FDA clearance for Phase II trial design featuring at-home patient self-administration, validating its potential as an outpatient therapy without the need for clinical monitoring.
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| References |
| Molecular Formula |
C21H26N2O3
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|---|---|
| Molecular Weight |
354.44
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| CAS # |
2930845-92-2
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| Related CAS # |
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)
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| Appearance |
Typically exists as solids at room temperature
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| Synonyms |
AAZ-A-154 benzoate; DTXSID901336869; AAZA154 Benzoate; AAZ-A-154 Benzoate; AAZA-154 Benzoate; RefChem:1075133; DTXCID001767164; AAZ-A 154 Benzoate; AAZ-A154 Benzoate; AAZA 154 Benzoate; DLX-001 Benzoate; DLX 001 Benzoate; DLX001 Benzoate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
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 Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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)] Oral Formulations
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 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8214 mL | 14.1068 mL | 28.2135 mL | |
| 5 mM | 0.5643 mL | 2.8214 mL | 5.6427 mL | |
| 10 mM | 0.2821 mL | 1.4107 mL | 2.8214 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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