Category: Uncategorized

  • ACP-105

    Plain-language summaryIntrigue 38 / 100

    ACP-105 is a tricyclic SARM from Acadia Pharmaceuticals that binds the androgen receptor with high affinity and shows the typical SARM profile of muscle and bone effects with reduced prostate activity in castrated rat models. Acadia briefly explored cognitive applications based on androgen receptor expression in the prefrontal cortex and hippocampus, but development never reached human trials. There are no published pharmacokinetic data in people. It is sold as a research chemical primarily on the strength of its name appearing in old patent literature. The evidence base is thin even by SARM standards. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity and tissue-selective anabolic profile

    A chlorinated aryl nitrile selective androgen receptor modulator discovered at ACADIA Pharmaceuticals through receptor selection and amplification technology screening, distinguished by partial agonist activity at the androgen receptor, tissue-selective anabolic effects on muscle and bone with minimal prostatic stimulation, and preclinical neuroprotective activity in irradiation and Alzheimer’s disease models.

    Abstract

    ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) is a nonsteroidal selective androgen receptor modulator (SARM) identified in 2006 at ACADIA Pharmaceuticals AB through high-throughput screening employing receptor selection and amplification technology (R-SAT) and published in the Journal of Medicinal Chemistry in 2009 as the lead compound of a novel aryl nitrile series [1]. The compound binds the androgen receptor with high affinity (pEC50 of 9.0 at the wild-type human androgen receptor and 9.4 at the clinically relevant T877A mutant) and functions as a partial agonist relative to the full agonist activity of testosterone and dihydrotestosterone [1]. In vitro, ACP-105 is reported to be as potent as testosterone in androgen receptor functional assays without measurable interaction at other steroid hormone receptors, including estrogen, progesterone, glucocorticoid, and mineralocorticoid receptors. In vivo, in a two-week chronic study in castrated male rats, the compound improved anabolic parameters (levator ani muscle mass) at approximately 66 percent of the efficacy of testosterone while producing only approximately 21 percent of the androgenic stimulation of the prostate, yielding a favorable anabolic-to-androgenic dissociation ratio of approximately 3:1 [1, 2].

    The compound crosses the blood-brain barrier with a reported brain-to-plasma ratio of 2.7, a property that has motivated investigation in central nervous system models [3, 4]. In a 2011 study by Dayger et al., subcutaneous administration of ACP-105 at 1 mg/kg/day to female C57BL/6J mice protected against 137-cesium irradiation-induced impairment of sensorimotor function on the rotarod and enhanced cued fear conditioning in both sham-irradiated and irradiated animals, with immunohistochemical evidence of region-specific modulation of microtubule-associated protein 2 (MAP-2) in the sensorimotor cortex [3]. In a 2013 study by George et al. in gonadectomized male triple-transgenic Alzheimer’s disease mice (3xTg-AD), ACP-105 at 10 mg/kg administered intraperitoneally four days per week reduced anxiety-like behavior when given alone and, when co-administered with the selective estrogen receptor beta agonist AC-186, improved long-term spatial memory on the Morris water maze, increased the amyloid-beta degrading enzymes neprilysin and insulin-degrading enzyme, and reduced brain amyloid-beta 40 and amyloid-beta 42 levels after seven months of treatment [4].

    Predicted and in silico absorption, distribution, metabolism, and excretion (ADME) profiling indicates high gastrointestinal absorption (94 to 100 percent), moderate lipophilicity (LogP 3.0 to 3.5), strong plasma protein binding (77 to 99 percent), and primary hepatic metabolism through CYP3A4 with secondary contributions from CYP2C19, CYP1A2, CYP2C9, and CYP2D6 [5]. In vivo metabolite identification studies in rats, horses, and humans have collectively characterized 21 or more phase I and phase II metabolites, predominantly monohydroxylated and bishydroxylated species formed on the azabicyclic ring system, along with glucuronide conjugates [6, 7, 8]. Predicted plasma half-life is approximately 1.18 hours, though this value derives from computational models and has not been confirmed in formal human pharmacokinetic studies [5].

    ACP-105 has never entered human clinical trials. No Phase 1, Phase 2, or Phase 3 studies are registered or reported. The compound was nominated as a development candidate by ACADIA Pharmaceuticals in February 2006 for potential treatment of muscle wasting and osteoporosis, and preclinical data were presented at the Experimental Biology 2008 meeting, but development was subsequently discontinued. The compound is classified as a prohibited substance under World Anti-Doping Agency (WADA) regulations since 2008, and adverse analytical findings for ACP-105 have appeared in routine sports doping control samples [6, 9]. Research-grade ACP-105 is available from multiple chemical suppliers at greater than 98 percent purity. This monograph reviews the chemistry, structure-activity relationships, and characterization of ACP-105; the androgen receptor partial agonist mechanism and tissue selectivity; the available absorption, distribution, metabolism, and excretion data; the preclinical pharmacology in musculoskeletal and central nervous system models; the absence of clinical evidence; sourcing and quality verification; reconstitution and handling; stack interaction considerations; adverse event and safety signals; and a comparative assessment of five alternative SARM compounds against ACP-105 on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Allopregnanolone

    Plain-language summaryIntrigue 80 / 100

    Allopregnanolone is a neurosteroid metabolite of progesterone that powerfully potentiates GABA-A receptors. Recombinant allopregnanolone (brexanolone) is FDA-approved for postpartum depression. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Endogenous neurosteroid and positive allosteric modulator of GABA-A receptors with dual synaptic and extrasynaptic activity

    An endogenous pregnane neurosteroid and the most potent known positive allosteric modulator of GABA-A receptors, reduced to clinical practice as brexanolone (Zulresso) for postpartum depression and serving as the pharmacophore template for the orally bioavailable derivative zuranolone.

    Abstract

    Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha,5alpha-tetrahydroprogesterone; brexanolone) is an endogenous C21 pregnane neurosteroid biosynthesized from progesterone by sequential 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase activity in the central nervous system, adrenal cortex, ovary, and placenta. First isolated from adrenal tissue in 1938 and identified as a potent positive allosteric modulator of GABA-A receptors by Majewska and colleagues in 1986, allopregnanolone occupies a singular position in neuropsychopharmacology as the most potent endogenous modulator of inhibitory GABAergic neurotransmission. At low nanomolar concentrations, the compound allosterically enhances GABA-gated chloride currents at both synaptic (alpha-beta-gamma-containing) and extrasynaptic (alpha-beta-delta-containing) GABA-A receptor subtypes; at higher micromolar concentrations, it directly gates the chloride channel in the absence of GABA. The extrasynaptic receptor preference distinguishes allopregnanolone from benzodiazepines and underlies its characteristic anxiolytic, anticonvulsant, sedative-hypnotic, and antidepressant pharmacology.

    The translational trajectory of allopregnanolone spans more than eight decades. Selye reported the anesthetic properties of pregnane steroids in 1941. Baulieu and colleagues proposed the “neurosteroid” concept in 1981 after demonstrating de novo brain synthesis independent of peripheral endocrine sources. Majewska et al. (1986) established the GABA-A receptor mechanism. Paul and Purdy (1992) coined “neuroactive steroid” to encompass synthetic analogs acting through non-genomic receptor modulation. The modern clinical program began at Sage Therapeutics, which developed an intravenous formulation of synthetic allopregnanolone (designated SAGE-547, later brexanolone) for postpartum depression (PPD). Two Phase 3 randomized, double-blind, placebo-controlled trials (Meltzer-Brody et al. 2018) demonstrated rapid, clinically meaningful, and sustained reductions in Hamilton Depression Rating Scale (HAM-D) scores following a 60-hour continuous intravenous infusion. The United States Food and Drug Administration approved brexanolone (Zulresso) in March 2019 as the first therapy specifically indicated for PPD, subject to a Risk Evaluation and Mitigation Strategy (REMS) program requiring inpatient administration with continuous pulse oximetry monitoring owing to the risks of excessive sedation and loss of consciousness.

    A parallel clinical program led by Roberta Diaz Brinton at the University of Arizona has investigated allopregnanolone as a regenerative therapeutic for Alzheimer’s disease, grounded in preclinical demonstrations that the compound promotes hippocampal neural stem cell proliferation, neurogenesis, oligogenesis, and restoration of cognitive function in transgenic Alzheimer’s models and wild-type aged mice. A Phase 1b/2a multiple ascending dose trial (NCT02221622) in early Alzheimer’s disease reported safety, tolerability, and exploratory neuroimaging signals including preservation of hippocampal volume and functional connectivity changes after 12 weeks of intermittent intravenous dosing. Additional clinical investigations have evaluated allopregnanolone in fragile X-associated tremor/ataxia syndrome (FXTAS), status epilepticus, traumatic brain injury, and essential tremor.

    The principal pharmacokinetic limitation of endogenous allopregnanolone is negligible oral bioavailability (less than 5 percent), necessitating intravenous, subcutaneous, or intramuscular administration. This limitation drove development of orally bioavailable synthetic analogs, most notably zuranolone (SAGE-217), a deuterated allopregnanolone analog approved by the FDA in August 2023 for PPD, and ganaxolone (3beta-methyl allopregnanolone), approved for seizures associated with CDKL5 deficiency disorder in March 2022. Allopregnanolone is metabolized by extra-hepatic non-CYP pathways, principally keto-reduction, glucuronidation, and sulfation, with an elimination half-life of approximately 9 hours after intravenous infusion, a volume of distribution of approximately 3 L/kg, and greater than 99 percent plasma protein binding. The compound is a controlled substance (Schedule IV in the United States). This monograph reviews the chemistry, biosynthesis, receptor pharmacology, pharmacokinetics, preclinical and clinical evidence base across all studied indications, sourcing and quality verification, reconstitution and handling, stack-interaction considerations, adverse-event profile, and a structured comparative assessment of five neurosteroid GABA-A receptor modulators against allopregnanolone on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Acetyl Glutathione

    Plain-language summaryIntrigue 38 / 100

    Acetyl glutathione is glutathione with an acetyl group attached to the cysteine sulfur, marketed in the supplement industry as a way to deliver intact glutathione orally. The proposed rationale is that the acetyl group protects the tripeptide from gastrointestinal proteolysis, allowing absorption of the full molecule rather than just its amino acid components. The case for meaningful intact absorption rests on small studies and biochemical reasoning rather than rigorous human pharmacokinetic data. Cheaper alternatives (NAC and direct oral glutathione) raise comparable cellular glutathione levels by different routes, making the niche for acetyl glutathione narrow. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    S-acyl thioester prodrug of reduced glutathione (gamma-L-glutamyl-L-cysteinyl-glycine)

    An acetylated thioester derivative of reduced glutathione engineered to resist gastrointestinal hydrolysis and deliver intact glutathione equivalents to the intracellular compartment via passive membrane permeation and subsequent cytoplasmic thioesterase-mediated deacetylation.

    Abstract

    S-Acetyl-L-glutathione (SAG) is the S-acyl thioester of reduced glutathione (GSH) in which a single acetyl group is conjugated to the sulfhydryl moiety of the cysteine residue, shielding it from oxidation and enzymatic degradation during gastrointestinal transit and systemic circulation. The modification addresses the central pharmacokinetic limitation of oral GSH supplementation: native reduced glutathione is rapidly hydrolyzed by gamma-glutamyltransferase and dipeptidases in the intestinal lumen and brush border, resulting in less than 1 percent systemic bioavailability of the intact tripeptide after oral dosing in humans. By masking the reactive thiol as a thioester, SAG transits the gut mucosa substantially intact, permeates cell membranes by passive diffusion, and is deacetylated intracellularly by cytoplasmic thioesterases to regenerate free reduced glutathione, thereby replenishing the intracellular GSH pool without dependence on de novo synthesis from precursor amino acids.

    The compound was first described in the medicinal chemistry literature as a glutathione S-acyl derivative in the 1970s, with early characterization of its sensitivity to human liver esterases. It entered the nutraceutical research field in the 2000s as a candidate oral glutathione delivery vehicle and has since been the subject of a single-center, single-dose, randomized, open-label, cross-over pharmacokinetic trial in 18 healthy volunteers (Fanelli et al., 2018), multiple preclinical studies in hepatoprotection and oncology, and a comprehensive toxicological safety assessment including bacterial reverse mutation assay, in vitro micronucleus testing, acute oral toxicity, and 13-week repeated-dose oral toxicity studies. The pharmacokinetic trial demonstrated that SAG is rapidly deacetylated to GSH after oral administration, with no quantifiable SAG detected in plasma at any time point; plasma GSH concentrations after SAG administration exhibited higher maximum concentration (Cmax) and area under the curve (AUC) compared to an equimolar dose of a marketed reduced glutathione product, with mean relative bioavailability exceeding that of the reference formulation.

    Preclinical pharmacology has demonstrated hepatoprotective activity against carbon tetrachloride-induced liver injury through restoration of superoxide dismutase activity, glutathione peroxidase activity, and mitochondrial function, with concurrent suppression of the TLR4/NF-kappaB inflammatory cascade and reduction of proinflammatory cytokines TNF-alpha, IL-6, IL-1beta, and MCP-1. In oncology research, SAG selectively induces apoptosis in human lymphoma cell lines (Daudi, Raji, Jurkat) through a paradoxical intracellular GSH depletion mechanism while sparing normal lymphocytes and resistant lymphoma lines (Hut-78), a selectivity that has positioned it as a research tool for mechanism-based apoptosis investigation. The compound is manufactured by selective S-acetylation of reduced glutathione, achievable in a single step with cobalt chloride catalysis in dimethylformamide-trifluoroacetic acid solvent at yields exceeding 90 percent, and is commercially available from multiple research-grade suppliers at purities exceeding 98 percent by HPLC. It is supplied as a white to off-white crystalline powder with a molecular weight of 349.36 g/mol (CAS 3054-47-5), melting point of approximately 202 to 208 degrees Celsius, and stability at ambient temperature in dry storage. This monograph reviews the chemistry, synthesis, pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing, handling, safety, and comparative assessment of SAG against five alternative glutathione-repletion strategies.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Alfaxalone

    Plain-language summaryIntrigue 68 / 100

    Alfaxalone is a synthetic neurosteroid IV anesthetic, originally combined with alfadolone in the human anesthetic Althesin (withdrawn 1984 after anaphylactoid reactions traced to the Cremophor solubilizer rather than the steroid). It was reformulated with a cyclodextrin solubilizer as Alfaxan and approved for veterinary use in dogs, cats, and rabbits. Structurally it mirrors the endogenous neurosteroid allopregnanolone. Mechanism is positive modulation of GABA-A receptors at a steroid binding site distinct from the benzodiazepine and barbiturate sites, with channel-opening activity at higher concentrations. Cardiovascular and respiratory profiles are favorable for an IV induction agent (less hypotension and apnea than propofol at induction doses), driving widespread veterinary use in cardiac-compromised patients. It serves as the canonical reference compound for synthetic neurosteroid GABA-A pharmacology, underpinning the design of brexanolone, ganaxolone, and zuranolone. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Neuroactive steroid general anesthetic and GABAA receptor positive allosteric modulator

    A synthetic pregnane neurosteroid originally developed by Glaxo as the active component of the intravenous anesthetic Althesin, reformulated in cyclodextrin carriers for veterinary registration and under active clinical investigation for human anesthesia with emerging evidence for neuroprotection and postoperative cognitive preservation.

    Abstract

    Alfaxalone (3-alpha-hydroxy-5-alpha-pregnane-11,20-dione) is a synthetic neuroactive steroid with potent general anesthetic properties mediated principally through positive allosteric modulation and, at higher concentrations, direct activation of gamma-aminobutyric acid type A (GABAA) receptors. First synthesized at the Glaxo UK Pharmacology Department in the late 1960s and introduced in 1971 as the principal active component of the intravenous anesthetic formulation Althesin (CT-1341), alfaxalone was administered in an estimated three million human anesthetic procedures across the United Kingdom, Europe, and other jurisdictions before its withdrawal from human clinical use in 1984 owing to anaphylactoid reactions attributed to the Cremophor EL solubilizing vehicle rather than to the active steroid itself. The compound was subsequently reformulated in 2-hydroxypropyl-beta-cyclodextrin (HPCD) by Jurox Animal Health and re-entered clinical practice as Alfaxan, a veterinary injectable anesthetic registered for induction and maintenance of general anesthesia in dogs and cats in Australia, New Zealand, the United Kingdom, continental Europe, the United States, and other jurisdictions. The HPCD formulation is devoid of the histamine-releasing properties of Cremophor EL and produces rapid-onset, short-duration, non-cumulative anesthesia with a cardiovascular safety profile superior to propofol in published comparative studies.

    Alfaxalone binds at the transmembrane beta-plus/alpha-minus subunit interface of GABAA receptors, a site structurally characterized by X-ray crystallography and cryo-electron microscopy of alpha1-beta3-gamma2 receptor assemblies. At sub-micromolar concentrations the compound potentiates GABA-evoked chloride conductance (positive allosteric modulation); at concentrations exceeding approximately one micromolar it directly gates the chloride channel in the absence of GABA (direct agonism). The composite dose-dependent pharmacology produces a continuum from anxiolysis and sedation through surgical anesthesia. Unlike the endogenous neurosteroid allopregnanolone and unlike classical progestogens, alfaxalone has no measurable activity at glucocorticoid, mineralocorticoid, or progesterone nuclear hormone receptors, a selectivity that simplifies its pharmacological profile and eliminates endocrine confounding in chronic or repeated dosing.

    A second molecular activity, characterized by in vitro studies from the Goodchild laboratory, is activation of the human pregnane X receptor (PXR) with greater efficacy than allopregnanolone. PXR activation drives transcription of brain-derived neurotrophic factor (BDNF) and other neuroprotective gene targets, providing a mechanistic basis for the observation in a double-blind randomized clinical trial that alfaxalone total intravenous anesthesia preserves postoperative serum mature BDNF levels and cognitive function relative to propofol and propofol-sevoflurane comparator arms (Serrao and Goodchild, 2022).

    Pharmacokinetics across species are dominated by rapid hepatic biotransformation. In dogs, plasma clearance after intravenous bolus is approximately 59 mL/kg/min (approaching hepatic blood flow), terminal elimination half-life is approximately 25 minutes, and volume of distribution is approximately 2.4 L/kg. In cats, clearance is approximately 25 mL/kg/min, half-life approximately 45 minutes, and volume of distribution approximately 1.8 L/kg. In the Phase 1 human trial of Phaxan (alfaxalone formulated in sulfobutylether-beta-cyclodextrin), plasma clearance was high and equal to hepatic blood flow, with rapid onset and offset of anesthesia comparable to propofol. The compound does not accumulate on repeated bolus dosing or continuous rate infusion at clinical doses, supporting its use for total intravenous anesthesia.

    Drawbridge Pharmaceuticals has advanced the human formulation (Phaxan) through Phase 1 dose-finding (Goodchild et al., 2019), a Phase 1c randomized double-blind comparison with propofol (Monagle et al., 2015), and a Phase 3 pilot study in hip arthroplasty (Serrao and Goodchild, 2022). Results demonstrate fast-onset, short-duration anesthesia with cognitive recovery comparable to propofol, less cardiovascular depression, less airway obstruction, and no pain on injection. The compound is not currently approved for human use in any jurisdiction. Additional research applications include anticonvulsant activity in refractory status epilepticus models, anxiolytic and sedative-hypnotic effects at sub-anesthetic doses, and neuroprotective activity through the PXR-BDNF pathway.

    This monograph documents the chemistry, synthesis, and stereochemistry of alfaxalone; the GABAA receptor pharmacology in structural and electrophysiological detail; the pregnane X receptor neuroprotective mechanism; comprehensive pharmacokinetics across species; the clinical and veterinary evidence base; sourcing and quality verification for research applications; reconstitution and handling; stack-interaction considerations; the adverse-event and safety signal; and a structured comparative assessment of five alternative intravenous anesthetic or neurosteroid agents (propofol, etomidate, ketamine, brexanolone, ganaxolone) against alfaxalone on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • 5-MeO-DMT

    Plain-language summaryIntrigue 76 / 100

    5-MeO-DMT is a tryptamine psychedelic chemically related to DMT but with strikingly different pharmacology: it prefers the 5-HT1A receptor over 5-HT2A, the opposite of N,N-DMT, which produces a qualitatively distinct experience generally described as an undifferentiated state rather than the visionary content of classical psychedelics. It is concentrated in the parotoid gland secretions of the Sonoran Desert toad (Bufo alvarius), the source of toad medicine ceremonies, and is found in several plants used in South American snuffs. Clinical interest in single-dose treatment for depression and substance use disorders is growing, with several small studies underway. The intensity and brevity of the experience pose unusual clinical and safety challenges. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Indolealkylamine tryptamine psychedelic with preferential 5-HT1A receptor agonism and broad serotonergic activity

    A naturally occurring 5-methoxy-substituted tryptamine distinguished from classical psychedelics by preferential high-affinity 5-HT1A receptor agonism, ultra-short duration of action, and emerging Phase 2 clinical evidence in treatment-resistant depression.

    Abstract

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT; CAS 1019-45-0; molecular formula C13H18N2O; molecular weight 218.30 g/mol) is a naturally occurring indolealkylamine tryptamine psychedelic first synthesized by Hoshino and Shimodaira in 1936, subsequently identified as a constituent of Anadenanthera peregrina seeds, Virola species bark resins, and the parotoid gland secretions of the Sonoran Desert toad Incilius alvarius (formerly Bufo alvarius). The compound is pharmacologically distinguished from other tryptamine psychedelics (N,N-dimethyltryptamine, psilocin, bufotenine) by a receptor binding profile that strongly favors the serotonin 5-HT1A receptor (Ki approximately 1.9 to 3 nM) over the 5-HT2A receptor (Ki approximately 900 nM), producing a 300- to 1000-fold selectivity ratio that inverts the binding preference of the classical 5-HT2A-preferring psychedelics. Functional pharmacology demonstrates full agonist activity at 5-HT1A receptors and partial to full agonism at 5-HT2A receptors, with additional binding at the serotonin transporter (SERT), sigma-1 receptors, and trace amine-associated receptor 1 (TAAR1).

    The subjective psychedelic experience produced by inhaled 5-MeO-DMT is characterized by a rapid onset (30 to 60 seconds), intense peak (5 to 15 minutes), and brief total duration (15 to 20 minutes), rendering the compound the shortest-acting of the classical tryptamine psychedelics. The ultra-short duration and the predominance of 5-HT1A-mediated pharmacology produce qualitative differences from 5-HT2A-preferring psychedelics: less visual perceptual distortion, more ego-dissolution and dissociative phenomenology, and high scores on mystical experience questionnaires comparable to high-dose psilocybin.

    Metabolism proceeds through two principal pathways. Monoamine oxidase A (MAO-A) catalyzes oxidative deamination to 5-methoxyindoleacetic acid, the primary inactivation route that accounts for the rapid systemic clearance and the oral inactivity of the compound in the absence of MAO inhibition. Cytochrome P450 2D6 (CYP2D6) catalyzes O-demethylation to bufotenine (5-hydroxy-N,N-dimethyltryptamine), a pharmacologically active metabolite with preferential 5-HT2A receptor affinity. CYP2D6 polymorphism substantially modulates the bufotenine metabolic fraction; poor metabolizers produce less bufotenine but experience prolonged parent compound exposure, while ultrarapid metabolizers generate more bufotenine with potential for additive serotonergic burden. The dual-enzyme metabolic architecture creates clinically significant drug-drug interactions, most critically with MAO inhibitors (harmine, harmaline, moclobemide, phenelzine, tranylcypromine), which increase 5-MeO-DMT systemic exposure 3.6- to 4.4-fold and bufotenine exposure 6.1- to 9.9-fold, with documented risk of serotonin toxicity and fatalities.

    Clinical development is led by GH Research (Dublin), whose inhalable mebufotenin formulation GH001 met the primary endpoint in a randomized, double-blind, placebo-controlled Phase 2b trial in 81 patients with treatment-resistant depression (TRD), demonstrating a placebo-adjusted Montgomery-Asberg Depression Rating Scale (MADRS) reduction of 15.5 points at day 8 and remission rates of 77.8 percent at 6 months in the open-label extension (announced February 2025). A Phase 1/2 open-label trial (Reckweg et al. 2023) in 12 TRD patients reported 87.5 percent remission at day 7 and no serious adverse events. Preclinical pharmacology demonstrates neuroplasticity effects including increased dendritic spine density in mouse medial frontal cortex, increased neurogenesis in the dentate gyrus, and anxiolytic effects in stressed animal models. The compound is classified as Schedule I in the United States, is not approved by any regulatory authority for medical use, and all research applications are subject to controlled substance research licensure. This monograph reviews the chemistry, natural occurrence, dual-enzyme metabolism, receptor pharmacology, pharmacokinetics, preclinical and clinical evidence, safety signal, sourcing, reconstitution, stack interactions, and a comparative assessment of five tryptamine psychedelic candidates against 5-MeO-DMT on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • ACE-031

    Plain-language summaryIntrigue 60 / 100

    ACE-031 is a soluble decoy receptor designed to soak up myostatin (the molecular brake on muscle growth) and related TGF-beta family ligands before they can engage real receptors on muscle. Built as a fusion of the activin receptor type IIB extracellular domain with an antibody Fc tail for half-life extension, it was developed at Acceleron Pharma for muscular dystrophy. Phase 1 and 2 trials demonstrated meaningful muscle mass increases but were halted in 2013 because of safety signals (epistaxis and gum bleeding, suggesting off-target effects on related TGF-beta ligands involved in vascular biology). The myostatin-trap concept lives on in related compounds. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Soluble activin receptor type IIB-Fc fusion protein (ActRIIB-IgG1 ligand trap) targeting myostatin and TGF-beta superfamily signaling

    A recombinant soluble decoy receptor comprising the extracellular domain of human activin receptor type IIB fused to the Fc domain of human immunoglobulin G1, developed by Acceleron Pharma as a systemic ligand trap for myostatin and related TGF-beta superfamily negative regulators of skeletal muscle mass.

    Abstract

    ACE-031 is a recombinant fusion protein composed of the extracellular domain of human activin receptor type IIB (ActRIIB) linked to the Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1), engineered to function as a circulating soluble decoy receptor that intercepts and neutralizes myostatin (growth and differentiation factor 8, GDF-8), activin A, activin B, GDF-11, and other transforming growth factor-beta (TGF-beta) superfamily ligands before they can engage their endogenous cell-surface receptors and transduce downstream Smad2/3-dependent signaling that constrains skeletal muscle growth. Developed by Acceleron Pharma (Cambridge, Massachusetts), ACE-031 was the first ActRIIB-Fc fusion protein to enter clinical trials in humans and the first systemic ligand trap approach to be tested in Duchenne muscular dystrophy (DMD), representing a pharmacological strategy that targets not a single ligand but the convergent signaling node through which multiple negative regulators of muscle mass operate.

    The foundational preclinical work was established by Lee and McPherron (2001) and Lee et al. (2005), who demonstrated that a soluble form of ActRIIB produced dramatic skeletal muscle hypertrophy in wild-type mice and caused additive muscle gains even in myostatin-null animals, indicating that ligands beyond myostatin contribute to muscle mass regulation through the ActRIIB pathway. Acceleron subsequently developed ACE-031 as a pharmaceutical-grade recombinant protein and advanced it through preclinical studies in mice and non-human primates that demonstrated robust increases in lean body mass, thigh muscle volume, individual muscle fiber cross-sectional area, and ex vivo contractile force, with concurrent improvements in bone mineral density and favorable effects on fat metabolism. A Phase 1 single ascending-dose study in 48 healthy postmenopausal women (Attie et al., 2013, Muscle and Nerve) established linear pharmacokinetics with a mean terminal half-life of 10 to 15 days, demonstrated statistically significant increases of 3.3 percent in total body lean mass and 5.1 percent in thigh muscle volume at the 3 mg/kg dose after a single subcutaneous injection, and characterized a favorable acute safety profile.

    The clinical development program advanced to a Phase 2 randomized, double-blind, placebo-controlled, ascending-dose trial in ambulatory, corticosteroid-treated boys with DMD (Campbell et al., 2017, Muscle and Nerve). The trial demonstrated trends toward increased lean body mass, increased bone mineral density, reduced fat mass, and maintenance of six-minute walk test distance in the ACE-031 groups compared to placebo, but was terminated after the second dosing cohort because of emergent vascular safety signals: epistaxis in 25 percent and mucocutaneous telangiectasias in approximately 21 percent of treated subjects. These events were subsequently attributed to the broad ligand-trapping profile of the unmodified ActRIIB extracellular domain, specifically the sequestration of bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), which are critical regulators of endothelial cell homeostasis and vascular integrity. In May 2013, Acceleron Pharma and Shire PLC concluded their collaboration and announced they would not restart development of ACE-031.

    The program’s discontinuation catalyzed two productive lines of successor development. Acceleron developed ACE-083, a follistatin-Fc fusion protein designed for local intramuscular injection that does not bind BMP9 or BMP10 and thus avoids the vascular signal. In parallel, the company developed luspatercept (ACE-536), a modified ActRIIB-Fc molecule with engineered ligand selectivity that avoids activin A and BMP trapping while retaining GDF-11 and GDF-8 neutralization, subsequently approved by the United States Food and Drug Administration for myelodysplastic syndrome-associated anemia and transfusion-dependent beta-thalassemia. ACE-031 itself is not approved by any regulatory authority for any indication. It remains available as a research-grade recombinant protein from chemical suppliers for in vitro and in vivo investigation of TGF-beta superfamily signaling, myostatin pathway biology, and muscle wasting pharmacology. Investigators should obtain analytical confirmation of identity, purity, and biological activity on every lot. This monograph documents the chemistry, mechanism of action, pharmacokinetics, preclinical pharmacology, clinical evidence, sourcing, handling, stack interactions, adverse-event profile, and comparative positioning of ACE-031 against five alternative myostatin/activin pathway inhibitors.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • J-147

    Phenyl hydrazide neurotrophic compound targeting mitochondrial ATP synthase alpha-F1 subunit with geroprotective and neuroprotective activity

    A synthetic curcumin-derived phenyl hydrazide developed at the Salk Institute through phenotypic screening against multiple age-associated neurotoxicities, identified as a partial modulator of mitochondrial ATP synthase alpha subunit (ATP5A) that activates the CAMKK2/AMPK longevity axis, with robust preclinical neuroprotection and cognitive reversal in aged Alzheimer’s disease mice and advancement to Phase 1 clinical evaluation.

    Abstract

    J-147 (CAS 1146963-51-0; molecular formula C18H17F3N2O2; molecular weight 350.33) is a synthetic phenyl hydrazide small molecule developed at the Salk Institute for Biological Studies in the laboratory of David Schubert through iterative phenotypic optimization beginning from the natural product curcumin. First reported by Chen et al. in 2011, J-147 was selected from a combinatorial chemical library on the basis of nanomolar potency across six cell-based assays modeling age-associated neurotoxicities: trophic factor withdrawal (EC50 25 nM), oxidative stress (EC50 10 to 200 nM), glucose starvation, chemical ischemia, and amyloid-beta 1-42 toxicity. The compound represents approximately 100-fold greater potency than its immediate precursor CNB-001 and vastly greater potency and bioavailability than curcumin itself, which was inactive in the selection assays at achievable concentrations.

    The molecular target of J-147 was identified in 2018 by Goldberg et al. as the alpha-F1 subunit of mitochondrial ATP synthase (ATP5A), using drug affinity responsive target stability (DARTS) and biotinylated affinity precipitation approaches. J-147 partially inhibits ATP synthase activity with an EC50 of approximately 20 nM and saturates at approximately 23.6 percent inhibition, producing a dose-dependent increase in cytosolic calcium that activates calcium/calmodulin-dependent protein kinase kinase beta (CAMKK2), which phosphorylates AMP-activated protein kinase (AMPK) at threonine 172. The resulting AMPK activation modulates mammalian target of rapamycin complex 1 (mTORC1) signaling, acetyl-CoA carboxylase 1 (ACC1) activity, and downstream metabolic pathways linked to both aging and neurodegeneration. ATP5A knockdown phenocopies J-147 across multiple neuroprotection assays, and J-147 provides no additional protection in ATP5A-knockdown cells, confirming target engagement specificity.

    In preclinical models, J-147 administered orally at 200 ppm in food (approximately 10 mg/kg/day) prevents cognitive decline in young APP/swePS1-deltaE9 transgenic mice over 7 months, preserves synaptic proteins (drebrin, synapsin-1, synaptophysin), reduces soluble amyloid-beta 1-40 and 1-42, increases brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), facilitates long-term potentiation at concentrations of 0.01 to 1 micromolar, and reduces oxidative stress and neuroinflammation markers. In aged (20-month) APP/PS1 mice, 3 months of J-147 treatment reverses established cognitive deficits in water maze, fear conditioning, and elevated plus maze paradigms. In the SAMP8 senescence-accelerated mouse model, J-147 attenuates age-associated hippocampal transcriptional drift by approximately 6 percent (P less than 10 to the negative 10). In Drosophila melanogaster, J-147 extends median lifespan by 9.5 to 12.5 percent.

    Pharmacokinetically, J-147 demonstrates 28 percent oral bioavailability in mice, a plasma half-life of 1.5 hours, a brain half-life of 2.5 hours, brain concentrations of approximately 600 nM at 2 hours after a 20 mg/kg oral dose (5- to 10-fold above its neuroprotective EC50), and a brain-to-plasma ratio of approximately 0.5. The compound is classified as having high blood-brain barrier penetration by the MDCK-MDRI cell culture model. Safety evaluation demonstrates no genotoxicity (Ames test negative to 0.36 mM), no acute toxicity in rats at 2 g/kg, no hERG channel inhibition, a CeeTox predicted toxicity value of 90 micromolar (yielding a therapeutic safety window of 782 to 3600-fold over efficacy concentrations), and no significant off-target activity across more than 60 CNS receptors, 352 protein kinases, and extensive enzyme panels. The sole notable off-target interactions are modest dopamine transporter (EC50 0.649 micromolar) and monoamine oxidase B (EC50 1.88 micromolar) activities at concentrations 6.5- to 19-fold above the neuroprotective range. A Phase 1 randomized double-blind placebo-controlled clinical trial (NCT03838185) was initiated in February 2019 by Abrexa Pharmaceuticals and completed in February 2020; results have not been published. The compound is not approved by any regulatory authority and is supplied exclusively as a research compound.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Navitoclax (ABT-263)

    Orally bioavailable BH3-mimetic inhibitor of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BCL-W) with senolytic and anti-fibrotic activity

    A first-in-class orally bioavailable BH3-domain mimetic developed at Abbott Laboratories that binds BCL-2, BCL-XL, and BCL-W with sub-nanomolar affinity, inducing mitochondrial apoptosis in malignant and senescent cells, and now advancing in combination with ruxolitinib in myelofibrosis.

    Abstract

    Navitoclax (ABT-263) is an orally bioavailable, small-molecule BH3-domain mimetic that binds with sub-nanomolar affinity to three anti-apoptotic members of the B-cell lymphoma 2 (BCL-2) protein family: BCL-2 (Ki less than or equal to 1 nM), BCL-XL (Ki less than or equal to 0.5 nM), and BCL-W (Ki less than or equal to 1 nM). The compound was developed at Abbott Laboratories (now AbbVie) as an orally bioavailable successor to the intravenous-only BH3 mimetic ABT-737, retaining the high-affinity, multi-target BCL-2 family binding of the parent molecule while achieving moderate oral bioavailability suitable for chronic dosing. Navitoclax occupies the hydrophobic BH3-binding groove on anti-apoptotic BCL-2 family members, displacing sequestered pro-apoptotic effectors BAX and BAK and thereby triggering mitochondrial outer membrane permeabilization, cytochrome c release, caspase activation, and intrinsic apoptosis in cells dependent on BCL-2 or BCL-XL for survival.

    The compound entered oncology clinical development in 2007. Phase 1 studies in chronic lymphocytic leukemia (CLL) demonstrated substantial single-agent activity, with an objective response rate of 31 percent and durable responses (median progression-free survival 25 months) in relapsed or refractory disease [1]. Phase 1 and Phase 2 studies in small-cell lung cancer (SCLC) and other solid tumors demonstrated limited single-agent activity, with an objective response rate of 2.6 percent in relapsed SCLC [2]. Clinical development as a single-agent oncologic therapy was constrained by mechanism-based, dose-limiting thrombocytopenia arising from BCL-XL inhibition in circulating platelets, which depend on BCL-XL for survival [3]. This on-target platelet toxicity motivated the development of the BCL-2-selective derivative venetoclax (ABT-199), which retains potent BCL-2 inhibition while sparing BCL-XL and thereby avoiding thrombocytopenia; venetoclax received FDA approval for CLL in 2016 and has become the foundational BCL-2-targeted agent in hematologic oncology.

    Navitoclax has continued in clinical development in combination regimens. The Phase 3 TRANSFORM-1 trial of navitoclax combined with the JAK1/JAK2 inhibitor ruxolitinib in treatment-naive myelofibrosis met its primary endpoint, demonstrating a spleen volume reduction of 35 percent or greater (SVR35) at week 24 in 63.2 percent of patients on the combination compared with 31.5 percent on ruxolitinib plus placebo [4]. The Phase 3 TRANSFORM-2 trial in relapsed or refractory myelofibrosis is ongoing with anticipated completion in late 2026. These results position navitoclax as a potential first-in-class BCL-2 family inhibitor approved for myelofibrosis.

    A second major research application emerged in 2016 with the identification of navitoclax as a potent senolytic agent. Senescent cells, which accumulate with aging and after genotoxic stress, upregulate BCL-XL and other anti-apoptotic BCL-2 family members as part of the senescence-associated apoptosis-resistance program. Zhu et al. (2016) and Chang et al. (2016) demonstrated that navitoclax selectively eliminates senescent cells in vitro and in vivo, rejuvenating aged hematopoietic stem cells, clearing senescent muscle stem cells, and improving vascular function in aged mice [5, 6]. The compound has since been characterized as anti-fibrotic in preclinical models of idiopathic pulmonary fibrosis, where it induces apoptosis in fibroblasts overexpressing BCL-2 family members and reverses established fibrosis [7]. These findings have positioned navitoclax as the prototype research senolytic and a pharmacological tool for investigating the contribution of cellular senescence to aging, fibrosis, and degenerative disease.

    Pharmacokinetics in humans are characterized by slow oral absorption (time to peak concentration approximately 7 to 9 hours), a terminal elimination half-life of approximately 15 to 17 hours, high plasma protein binding (greater than 99 percent), and low volume of distribution (0.5 to 0.7 L/kg). The compound is metabolized by CYP3A4 and is a moderate inhibitor of CYP2C8 and a strong inhibitor of CYP2C9. Approximately 90 percent of the administered dose is excreted in feces, with approximately half as metabolites. A high-fat meal increases oral exposure by approximately 70 percent. The compound is not approved by any regulatory authority for any indication. It is available as a research-grade preparation from multiple chemical suppliers. Investigators should obtain analytical confirmation of identity and purity on every lot.

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  • ANAVEX 3-71

    Dual allosteric M1 muscarinic acetylcholine receptor agonist and sigma-1 receptor agonist

    A spirocyclic thiadiazine-piperidine compound developed at the Israel Institute for Biological Research as a dual allosteric M1 muscarinic and sigma-1 receptor agonist, distinguished by sub-nanomolar allosteric potency at M1, disease-modifying preclinical efficacy in transgenic Alzheimer’s disease models, and active clinical development across schizophrenia, frontotemporal dementia, and Alzheimer’s disease indications.

    Abstract

    ANAVEX 3-71 (development code AF710B; CAS 1235733-73-9) is a synthetic spirocyclic thiadiazine-piperidine compound and a dual allosteric agonist at the M1 subtype of the muscarinic acetylcholine receptor and the sigma-1 receptor (SIGMAR1). The compound was invented by Abraham Fisher at the Israel Institute for Biological Research (IIBR) in Ness Ziona, Israel, as the fourth generation of a series of cholinergic agonists (AF102B, AF267B, AF292, AF710B) with progressively greater selectivity and allosteric character at the M1 muscarinic receptor. ANAVEX 3-71 emerged from high-throughput receptogram profiling as a compound with sub-nanomolar allosteric binding affinity at M1 muscarinic receptors (approximately 0.05 nM) and nanomolar affinity at the sigma-1 receptor (Ki approximately 1.3 nM), with no agonistic activity at M2 through M5 muscarinic subtypes, no significant binding at alpha-4-beta-2 or alpha-7 nicotinic receptors, and a clean off-target profile across 83 additional G-protein-coupled receptors, ion channels, and transporters screened at 10 micromolar. The preclinical pharmacology of ANAVEX 3-71 has been characterized principally in three studies using transgenic rodent models of Alzheimer’s disease. Fisher et al. (2016) reported that AF710B at 10 micrograms per kilogram per day intraperitoneally for two months in 3xTg-AD mice reversed cognitive deficits in the Morris water maze, decreased BACE1, GSK3-beta activity, and tau phosphorylation at multiple epitopes (AT180, AT270, PHF-1), reduced soluble and insoluble amyloid-beta 40 and 42, and rescued mushroom dendritic spine loss in hippocampal neuronal cultures at 30 nanomolar. Hall et al. (2018) extended these findings to McGill-R-Thy1-APP transgenic rats, demonstrating that oral treatment at 10 micrograms per kilogram per day for 4.5 months at 13 months of age (postplaque) reverted cognitive deficits, reduced amyloid pathology and neuroinflammation, and increased cerebrospinal fluid amyloid clearance, with effects maintained following a 5-week treatment interruption consistent with disease-modifying rather than symptomatic activity. Orciani et al. (2023) demonstrated that early (preplaque, 7 months of age) treatment at the same dose for 7 months prevented cognitive impairment, reduced hippocampal plaque burden and cortical amyloid-beta peptides, attenuated microglial and astrocytic neuroinflammation, and rescued pro-BDNF to mature BDNF conversion, with effects persisting through a 4-week washout. Human pharmacokinetics characterized in a Phase 1 single ascending dose study (NCT04442945; 36 healthy volunteers; 5 to 200 mg) demonstrate linear, dose-proportional, and time-invariant pharmacokinetics with a mean apparent terminal elimination half-life of 3.56 hours for the parent compound and 6.59 hours for the M8 metabolite. No clinically relevant effects on QTc or other electrocardiographic parameters were observed across the full studied dose range. Food had no effect on the pharmacokinetics of ANAVEX 3-71 or its M8 metabolite. Clinical development is ongoing across multiple indications. A Phase 2 study in schizophrenia (NCT06245213; 71 subjects) reported dose-dependent improvements in electroencephalographic biomarkers and favorable safety and tolerability with no serious treatment-emergent adverse events. A modified-release oral tablet enabling once-daily dosing was successfully developed in a Phase 1b study completed in October 2025. ANAVEX 3-71 is not approved by any regulatory authority and is supplied as a research-grade preparation. This monograph reviews the chemistry, dual-receptor pharmacology, preclinical pharmacology in transgenic Alzheimer’s models, human pharmacokinetics, the clinical evidence base, sourcing and quality verification, handling considerations, interaction profile, adverse event signal, and a comparative assessment of five mechanistically related compounds against ANAVEX 3-71 on five competency standards.

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