AAZ-A-154

AAZ-A-154, subsequently designated DLX-001 and assigned the international nonproprietary name zalsupindole, is a substituted isotryptamine derivative that acts as a low-potency, low-efficacy partial agonist of the serotonin 5-HT2A receptor (EC50 approximately 8,200 nM; Emax approximately 17 percent of serotonin maximum) and a moderate-efficacy partial agonist of the 5-HT2C receptor (EC50 approximately 3,300 nM; Emax approximately 70 percent), with silent antagonism at the 5-HT2B receptor and selectivity for serotonergic over dopaminergic, adrenergic, and opioid targets. The compound was first synthesized in 2019 in the laboratory of David E. Olson at the University of California, Davis, and was identified from a library screen using psychLight, a genetically encoded fluorescent biosensor constructed from the human 5-HT2A receptor with a circularly permuted green fluorescent protein inserted into the third intracellular loop [1]. PsychLight discriminated hallucinogenic from non-hallucinogenic 5-HT2A ligands on the basis of differential conformational activation signatures, and AAZ-A-154 was selected as a lead compound on the basis of its favorable ligand score, a metric that predicted non-hallucinogenic character despite retention of 5-HT2A-dependent psychoplastogenic activity.

The compound is structurally related to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) but is an isotryptamine (the aminoalkyl side chain is attached to the indole nitrogen at position 1 rather than at position 3), a modification that repositions the compound in chemical space outside classical psychedelic tryptamines. The (R)-enantiomer is the active form; the alpha-methyl substituent on the aminoalkyl chain confers metabolic stability and enantioselective receptor engagement. In rodent models, AAZ-A-154 at doses of 15 to 20 mg/kg intraperitoneally produced rapid-onset (30 minutes) and sustained (7 to 14 days) antidepressant-like behavioral effects in the forced swim test and in the sucrose preference test in VMAT2 heterozygous mice, a genetic model of depressive phenotype [1]. The compound increased dendritic arbor complexity in cultured embryonic rat cortical neurons to a degree comparable to ketamine, and the neuroplastogenic effect was abolished by the 5-HT2 receptor antagonist ketanserin, confirming receptor dependence [1]. Critically, AAZ-A-154 failed to produce the head-twitch response in mice at doses up to 100 mg/kg, the standard behavioral proxy for hallucinogenic activity in the 5-HT2A agonist class [1].

A comprehensive preclinical characterization published by Agrawal et al. (2025) in ACS Chemical Neuroscience demonstrated that zalsupindole promoted cortical neuritogenesis in vitro, increased dendritic spine density in the prefrontal cortex in vivo, and enhanced measures of functional plasticity to a degree comparable to or greater than ketamine, psilocybin, and N,N-dimethyltryptamine, despite lacking any of the acute cellular and behavioral characteristics of hallucinogenic or dissociative compounds [2]. Pharmacokinetic studies revealed high brain penetrance, rapid distribution, and rapid clearance. In Phase 1 clinical trials enrolling 106 healthy volunteers, oral zalsupindole was well tolerated across a dose range of 2 to 360 mg, with no reports of psychotomimetic, hallucinogenic, or dissociative effects, and with quantitative electroencephalography demonstrating measurable changes in cortical activity consistent with target engagement [3, 4]. A Phase 1b study in 18 adults with major depressive disorder reported clinically meaningful reductions in Montgomery-Asberg Depression Rating Scale scores of approximately 12 points (approximately 50 percent improvement) by Day 8, with effects maintained through Day 36, and comparable efficacy between a seven-day once-daily regimen and a two-dose regimen [5]. No serious adverse events were reported across more than 120 individuals studied. Dose-dependent nausea, headache, and dizziness were the principal mild adverse events. In October 2025, the United States Food and Drug Administration cleared the Investigational New Drug application for a Phase 2, multi-site, randomized, double-blind, placebo-controlled trial in major depressive disorder featuring at-home self-administration [5]. This monograph reviews the chemistry, biosensor-guided discovery, receptor pharmacology, neuroplasticity mechanisms, pharmacokinetics, preclinical and clinical evidence, sourcing and handling, stack interactions, adverse-event signal, and a comparative assessment of five psychoplastogen and rapid-acting antidepressant candidates against AAZ-A-154.