Author: kodiac

  • LPH-5

    Selective serotonin 5-HT2A receptor partial agonist of the 2,5-dimethoxyphenylpiperidine structural class

    A conformationally restricted phenethylamine psychedelic developed at Lophora ApS as a highly selective 5-HT2A receptor partial agonist with robust and persistent antidepressant-like activity in rodent models, distinguished from classical psychedelics by pronounced subtype selectivity over the serotonin 5-HT2B and 5-HT2C receptors and currently in Phase 1 clinical evaluation for treatment-resistant depression.

    Abstract

    LPH-5, the (S)-enantiomer of 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and a conformationally restricted analog of the phenethylamine psychedelic 2C-TFM, is a potent and selective partial agonist of the serotonin 5-hydroxytryptamine type 2A (5-HT2A) receptor under clinical development for treatment-resistant depression and potentially other neuropsychiatric indications. First disclosed in a 2021 patent assigned to Lophora ApS and characterized in the peer-reviewed literature by Marcher-Rorsted et al. (2024) in the Journal of Medicinal Chemistry, LPH-5 emerged from a systematic structure-activity relationship exploration of 2,5-dimethoxyphenylpiperidines in which cyclization of the flexible phenethylamine chain into a piperidine ring, combined with the 4-trifluoromethyl substituent, produced a compound with low-nanomolar 5-HT2A receptor binding affinity (Ki 1.3 nM against [125I]DOI), potent functional partial agonism in calcium mobilization assays (EC50 3.2 nM, Emax approximately 92 percent of the serotonin maximum at the 5-HT2A receptor), and approximately 60-fold functional selectivity for 5-HT2A over the 5-HT2B receptor, with no measurable agonist activity at the 5-HT2C receptor at concentrations up to 30 micromolar in receptor internalization assays. This selectivity profile distinguishes LPH-5 from classical serotonergic psychedelics such as psilocin, lysergic acid diethylamide, and N,N-dimethyltryptamine, all of which activate the 5-HT2B and 5-HT2C receptors at therapeutically relevant concentrations, and from the parent compound 2C-TFM, which retains substantial 5-HT2C agonist activity.

    In preclinical pharmacology, LPH-5 dose-dependently induces the head-twitch response in rodents, a behavioral correlate of 5-HT2A receptor activation and a proxy for psychedelic potential, confirming central target engagement after systemic administration. The compound produces robust acute and persistent antidepressant-like effects in the rat forced swim test, with reduction in immobility observed both at 24 hours and at 7 days after a single administration, a temporal profile consistent with the sustained antidepressant responses reported in clinical trials of psilocybin. The stereochemistry is critical: the (S)-enantiomer (designated the eutomer) is consistently more potent at the 5-HT2A receptor and more selective against the 5-HT2C receptor than the corresponding (R)-distomer across the entire 2,5-dimethoxyphenylpiperidine series. Absolute configuration was confirmed by X-ray crystallography. Physicochemical properties are favorable for central nervous system drug development, with a LogP of 3.45, high membrane permeability (MDR1-MDCKII efflux ratio 0.94), and ligand efficiency metrics (LE 0.6, LLE 5) that position the compound in the optimal drug-like space.

    Preclinical toxicology studies completed at Lophora reported no toxicology or histopathology findings, and all chemistry, manufacturing, and controls activities were completed by 2022. The European Medicines Agency authorized a Phase 1 first-in-human clinical trial in September 2024. The trial, a randomized placebo-controlled single- and multiple-ascending-dose study in healthy volunteers conducted at Biotrial in Rennes, France, began dosing subjects in May 2025, with topline results expected in the fourth quarter of 2025. LPH-5 is designed for use in psychedelic-assisted psychotherapy and represents a pharmacological strategy in which the therapeutic benefits of classical psychedelics are pursued through a compound with improved receptor subtype selectivity, reduced 5-HT2B-associated cardiac risk, and a defined stereochemical identity. This monograph reviews the chemistry, stereochemistry, and structure-activity relationships of LPH-5; the in vitro and in vivo pharmacology at serotonin receptor subtypes; the preclinical behavioral pharmacology; the development history and clinical trajectory; sourcing, reconstitution, and handling considerations for laboratory use; stack interactions; adverse-event expectations; and a structured comparative assessment of five alternative 5-HT2A receptor agonists (psilocybin/psilocin, 25CN-NBOH, DOI, LSD, and the non-hallucinogenic analog tabernanthalog) against LPH-5 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.

  • Thymalin

    Plain-language summaryIntrigue 58 / 100

    Thymalin is a Russian-developed bovine thymus peptide preparation used as an immunomodulator for elderly patients and immune disorders. Combined with epitalon in Khavinson’s longevity research. 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.

    Thymic polypeptide bioregulator complex with immunomodulatory and geroprotective activity

    A heterogeneous polypeptide complex isolated from calf thymus, developed at the Military Medical Academy in Leningrad as a thymic bioregulator for immune restoration, distinguished from other thymic peptide preparations by its multicomponent composition containing the immunomodulatory dipeptides L-glutamyl-L-tryptophan and L-lysyl-L-glutamic acid and the tripeptide L-glutamyl-L-aspartyl-L-proline.

    Abstract

    Thymalin is a standardized polypeptide complex isolated from the thymus gland of calves by acid hydrolysis and ultrafiltration, containing peptide fractions in the 1,000 to 10,000 dalton molecular weight range. Developed at the Military Medical Academy in Leningrad (now Saint Petersburg) by Vladimir Khavinson and Vyacheslav Morozov in the 1970s, the preparation was registered as an immunomodulatory pharmaceutical in the Soviet Union in 1982 and has remained in clinical use in the Russian Federation for more than four decades. Unlike the structurally defined thymic peptides thymosin alpha-1 (a 28-amino-acid single-sequence peptide), thymulin (a zinc-dependent nonapeptide), and thymopentin (a synthetic pentapeptide fragment of thymopoietin), Thymalin is a multicomponent extract whose principal bioactive constituents have been identified by reversed-phase high-performance liquid chromatography as the dipeptide L-glutamyl-L-tryptophan (Glu-Trp, subsequently developed independently as Thymogen), the dipeptide L-lysyl-L-glutamic acid (Lys-Glu, developed as Vilon), and the tripeptide L-glutamyl-L-aspartyl-L-proline (Glu-Asp-Pro, developed as Crystagen). The molecular mechanism of the immunoprotective activity is attributed to the capacity of these short peptides to bind selectively to double-stranded DNA sequences and to histone proteins, thereby modulating chromatin conformation, gene expression, and the synthesis of immune system proteins including interleukins, interferons, heat-shock proteins, and components of the fibrinolytic system. In experimental systems, Thymalin stimulates the differentiation and functional activity of T-lymphocyte subpopulations (CD4+ and CD8+), normalizes the ratio of T-helper to T-suppressor cells, enhances natural killer cell activity and phagocytosis, and modulates the balance between pro-inflammatory and anti-inflammatory cytokines. The geroprotective properties of Thymalin are supported by a prospective clinical observation of 266 elderly subjects over 6 to 8 years conducted at the St. Petersburg Institute of Bioregulation and Gerontology and the Institute of Gerontology of the Ukrainian Academy of Medical Sciences, in which Thymalin-treated subjects exhibited 2.0- to 2.1-fold lower mortality compared to controls receiving standard geriatric care, with further reductions (4.1-fold lower mortality) observed in a subgroup receiving annual combined Thymalin and Epithalamin treatment for 6 years. More recently, a prospective randomized single-blind controlled trial of Thymalin (10 mg intramuscular daily for 10 days) in 80 elderly patients with severe COVID-19 reported a 92 percent increase in blood lymphocytes, 6.5-fold reduction in interleukin-6, halved in-hospital mortality (19.4 percent versus 40.9 percent in controls), and more rapid clinical improvement (80.5 percent versus 59 percent). In vitro studies have demonstrated that Thymalin reduces expression of the stem cell markers CD44 and CD117 by 2- to 3-fold while increasing expression of CD28 (a marker of mature T lymphocytes) by 6.8-fold, consistent with stimulation of hematopoietic stem cell differentiation into functional T cells. The compound is administered by intramuscular or subcutaneous injection in short cyclical courses of 5 to 10 days at doses of 5 to 10 mg daily, with clinical effect reported to persist for weeks to months following each treatment course. The safety record across more than 40 years of clinical use indicates minimal adverse events, principally limited to injection-site reactions. This monograph reviews the composition, extraction, and characterization of Thymalin; the molecular pharmacology of its constituent peptides at the level of DNA binding, histone interaction, and gene expression regulation; the pharmacokinetic properties; the preclinical evidence base across immune restoration, geroprotection, and oncology models; the clinical evidence in elderly immune decline, respiratory infections, perioperative immune suppression, and COVID-19; sourcing and quality verification considerations; reconstitution and handling protocols; stack interactions with other immunomodulatory agents; the adverse-event and safety profile; and a comparative assessment of five alternative thymic and immunomodulatory peptide preparations against Thymalin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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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.

  • Cerebrolysin

    Plain-language summaryIntrigue 65 / 100

    Cerebrolysin is a porcine brain peptide hydrolysate used in Europe and Asia for stroke recovery and dementia. It contains a complex mixture of small peptides and amino acids. Available only as injection. 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.

    Porcine brain-derived neurotrophic peptide mixture with multimodal neuroprotective and neurorestorative activity

    A standardized enzymatic hydrolysate of porcine brain tissue yielding low-molecular-weight neuropeptides and free amino acids that cross the blood-brain barrier and exert neurotrophic, neuroprotective, and neuroplasticity-promoting effects across stroke, traumatic brain injury, and neurodegenerative disease models.

    Abstract

    Cerebrolysin is a standardized, injectable preparation of enzymatically derived low-molecular-weight neuropeptides and free amino acids obtained from porcine brain tissue, manufactured by EVER Neuro Pharma (formerly EBEWE Pharma) in Unterach, Austria. The preparation contains peptide fragments exclusively below 10,000 Daltons in molecular weight, including sequences homologous to brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF), together with approximately 15 percent free amino acids by mass. First developed in 1949 by Gerhard Harrer at the University of Graz and subsequently refined through enzymatic hydrolysis standardization at EBEWE Pharma beginning in 1972, the compound has been registered as a pharmaceutical product in over 50 countries (excluding the United States, Canada, the United Kingdom, and most Western European Union member states) for indications including stroke recovery, traumatic brain injury, and dementia syndromes.

    The pharmacological profile of Cerebrolysin is characterized by multimodal neurotrophic and neuroprotective activity. The constituent peptides activate tropomyosin receptor kinase (Trk) signaling pathways, particularly TrkA and TrkB, initiating downstream MAPK/ERK and PI3K/Akt cascades that regulate neuronal survival, differentiation, and synaptic plasticity. Additional characterized mechanisms include inhibition of calpain-mediated cytoskeletal degradation, suppression of excitotoxic glutamate signaling, reduction of free radical formation, attenuation of microglial activation, and promotion of neurogenesis in the subventricular zone and hippocampal dentate gyrus. The low molecular weight of the constituent peptides permits transit across the blood-brain barrier, a property that distinguishes Cerebrolysin from recombinant full-length neurotrophic factors that do not achieve meaningful central nervous system concentrations after peripheral administration.

    The clinical evidence base encompasses more than 200 clinical studies involving over 10,000 patients across stroke, traumatic brain injury, Alzheimer’s disease, vascular dementia, and pediatric neurodevelopmental indications. The Cerebrolysin and Recovery After Stroke (CARS) randomized, placebo-controlled, double-blind multicenter trial demonstrated large superiority of Cerebrolysin (30 mL per day for 21 days) over placebo on the Action Research Arm Test at day 90 (Mann-Whitney estimator 0.71, 95 percent confidence interval 0.63 to 0.79, P less than 0.0001). The Cerebrolysin Acute Stroke Treatment in Asia (CASTA) trial in 1,070 patients did not demonstrate superiority on the primary endpoint (National Institutes of Health Stroke Scale at day 90), although post hoc analysis in severe stroke (NIHSS greater than 12) showed a trend favoring Cerebrolysin. In Alzheimer’s disease, a meta-analysis of randomized controlled trials demonstrated significant improvement in cognitive function (standardized mean difference negative 0.40 on the ADAS-cog at 4 weeks) and global clinical change compared to placebo, with safety comparable to placebo. In traumatic brain injury, 27 clinical studies enrolling 9,752 patients have demonstrated improvements in consciousness level, cognitive performance, and neurological outcomes.

    The safety profile across controlled clinical trials is favorable, with adverse event rates comparable to placebo in most analyses. The principal adverse events are vertigo, agitation, feeling hot, headache, and dizziness. Rare anaphylactic reactions have been reported. The compound is contraindicated in epilepsy and severe renal impairment. This monograph reviews the composition, manufacturing, and quality standardization of Cerebrolysin; the multimodal neurotrophic and neuroprotective pharmacology; the pharmacokinetic profile including blood-brain barrier penetration; the clinical evidence base across all studied indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a comparative assessment of five neurotrophic or neuroprotective alternatives (Cortexin, P21, NSI-189, Actovegin, Semax) against Cerebrolysin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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  • 1,3-DMAA

    Synthetic aliphatic sympathomimetic amine with indirect adrenergic and dopaminergic activity

    A branched-chain aliphatic amine originally developed by Eli Lilly as the inhaled nasal decongestant Forthane, subsequently repurposed as an ergogenic dietary supplement ingredient, and characterized pharmacologically as an indirect sympathomimetic acting principally through norepinephrine and dopamine release with substrate-like dopamine transporter regulation.

    Abstract

    1,3-Dimethylamylamine (1,3-DMAA; 4-methylhexan-2-amine; methylhexanamine) is a synthetic aliphatic sympathomimetic amine first introduced by Eli Lilly and Company in 1944 under the trade name Forthane as an inhaled nasal decongestant and voluntarily withdrawn from the market in 1983. The compound re-entered commercial circulation in 2006 when it was marketed as an ergogenic dietary supplement ingredient under the name Geranamine, following the regulatory removal of ephedrine alkaloids from the United States supplement market in 2004. The pharmacology of 1,3-DMAA is that of an indirect sympathomimetic: the compound acts as a norepinephrine and dopamine releasing agent, inhibits the norepinephrine transporter (NET) at low micromolar concentrations, and exhibits substrate-like regulation of the dopamine transporter (DAT) including competitive inhibition of dopamine uptake, binding at the S1 substrate site, induction of outward-facing-open to outward-facing-closed conformational transitions, and stimulation of DAT endocytosis through cocaine- and protein kinase A-sensitive mechanisms. These monoaminergic actions produce dose-dependent cardiovascular stimulation (vasoconstriction, elevation of systolic and diastolic blood pressure, tachycardia), central nervous system arousal, and thermogenic effects consistent with the broader sympathomimetic amine class that includes ephedrine, amphetamine, and phenylpropanolamine.

    The sole formal human pharmacokinetic study (Schilling et al., 2013; n = 7 healthy men; single oral dose of 25 mg) reported a peak plasma concentration of approximately 70 ng/mL, time to peak of 3.57 hours, terminal elimination half-life of 8.45 hours, oral clearance of 20.02 L/hr, and volume of distribution of 236 L, indicating extensive tissue partitioning. Physiological monitoring in that study documented modest increases in heart rate and diastolic blood pressure that remained within normal clinical ranges at the 25 mg dose. However, case reports and postmarketing surveillance have associated substantially higher doses of 1,3-DMAA (often in combination with caffeine and other stimulants in multi-ingredient pre-workout and weight-loss supplements) with serious cardiovascular events including cerebral hemorrhage, myocardial infarction, cardiac arrest, hepatotoxicity, and death. The United States Food and Drug Administration has received at least 86 reports of illness and death associated with DMAA-containing supplements and has determined that 1,3-DMAA is not a dietary ingredient; its inclusion in products marketed as dietary supplements is unlawful under United States federal law. Preclinical abuse liability assessment (Dolan and Gatch, 2015) demonstrated that 1,3-DMAA fully substituted for cocaine and partially substituted for methamphetamine in drug discrimination assays, produced conditioned place preference in mice at intermediate doses, and generated dose-dependent locomotor depression, indicating psychostimulant-like abuse potential.

    The compound is banned or restricted in the United States, Canada, Australia, New Zealand, the United Kingdom, Brazil, Sweden, Finland, and Switzerland, and is listed as a prohibited substance by the World Anti-Doping Agency. It is not approved as a medicine in any jurisdiction as of the date of this monograph. This monograph reviews the chemistry, synthesis, and structural classification of 1,3-DMAA; the historical development and regulatory trajectory; the molecular pharmacology at monoamine transporters and adrenergic receptors; the limited human pharmacokinetic record; preclinical pharmacology including abuse liability; the clinical and adverse-event evidence base; sourcing and analytical verification considerations; reconstitution and handling; stack interaction and combination risks; the comprehensive adverse-event and safety signal; and a comparative assessment of five sympathomimetic amine stimulants against 1,3-DMAA on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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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.

  • Primobolan

    Synthetic androstane anabolic-androgenic steroid; 1-methyl dihydrotestosterone derivative with moderate androgen receptor agonism

    A non-17-alpha-alkylated dihydrotestosterone derivative developed by Squibb and Schering for refractory anemia and catabolic wasting, distinguished from other anabolic-androgenic steroids by its favorable hepatic safety profile, absence of aromatization, and moderate anabolic-to-androgenic dissociation.

    Abstract

    Primobolan is the trade name for metenolone (also rendered methenolone), a synthetic androstane steroid derived from dihydrotestosterone (DHT) by introduction of a 1-methyl group and a 1,2-double bond into the A-ring of the 5-alpha-reduced androstane nucleus. The compound was first synthesized in 1960 and introduced for clinical use in 1961 by Squibb Pharmaceuticals in the United States (as Nibal and Nibal Depot) and by Schering AG in West Germany (as Primobolan and Primobolan Depot). Two ester prodrug forms are manufactured: metenolone acetate (CAS 434-05-9), the oral preparation with a molecular weight of 344.50 g/mol, and metenolone enanthate (CAS 303-42-4), the intramuscular depot preparation with a molecular weight of 414.63 g/mol. Both esters undergo hydrolysis in vivo to release the parent steroid metenolone (CAS 153-00-4; molecular formula C20H30O2; molecular weight 302.46 g/mol), which binds the androgen receptor with moderate affinity and produces anabolic effects in skeletal muscle, bone, and erythropoietic tissue.

    The clinical pharmacology of metenolone is defined by several characteristics that distinguish it from structurally related anabolic-androgenic steroids. First, the compound is not 17-alpha-alkylated; the 1-methyl substitution and ester conjugation confer sufficient oral bioavailability (in the acetate form) and depot duration (in the enanthate form) without the hepatotoxic liability associated with C17-alpha-alkylated steroids such as oxymetholone, stanozolol, and methandrostenolone. Second, the 1,2-double bond and the DHT-derived backbone render metenolone resistant to aromatization by the cytochrome P450 aromatase enzyme complex (CYP19A1), eliminating estrogenic side effects including gynecomastia and estrogen-mediated fluid retention. Third, metenolone exhibits a moderate anabolic-to-androgenic dissociation ratio of approximately 88:44 to 150:50 in rodent bioassays (levator ani weight gain versus ventral prostate weight gain, relative to testosterone propionate as the reference standard), placing it in the class of mildly anabolic, mildly androgenic agents alongside oxandrolone and drostanolone.

    The principal approved clinical indication was the treatment of anemia due to bone marrow failure, including aplastic anemia, myelofibrosis, and refractory cytopenias. A therapeutic trial reported by Compagno et al. (1978) in 19 consecutive patients with refractory anemia demonstrated remission in approximately 37 percent of patients with pancytopenia and variable responses across other cytopenia subtypes [1]. Additional historical indications included protein-calorie malnutrition, postoperative and post-infectious catabolic states, osteoporosis, sarcopenia, and promotion of weight gain in premature infants. The compound has been largely discontinued from clinical markets; as of the most recent monograph revision, metenolone enanthate is marketed only in Spain and Turkey (as Primobolan Depot), and metenolone acetate retains limited availability in Japan and Moldova.

    Pharmacokinetics differ substantially between the two ester forms. Metenolone acetate is rapidly absorbed after oral administration but undergoes significant first-pass hepatic metabolism, resulting in reduced oral bioavailability relative to parenteral administration; the plasma half-life of the oral form is approximately 4 to 6 hours. Metenolone enanthate, administered by intramuscular injection in an oil vehicle, provides depot release with a biological half-life of approximately 10.5 days and a duration of action of approximately 14 days. Metabolism of metenolone proceeds through hepatic mixed-function oxidases; the principal urinary metabolite is 3-alpha-hydroxy-1-methylen-5-alpha-androstan-17-one, excreted as glucuronide and sulfate conjugates. The sulfate-conjugated metabolites provide extended detection windows in anti-doping analysis, with some metabolites detectable for several weeks after a single administration. Metenolone exhibits low affinity for sex hormone-binding globulin (SHBG), approximately 16 percent of that of testosterone and 3 percent of that of DHT, resulting in a higher fraction of unbound drug in plasma.

    Adverse effects are consistent with the anabolic-androgenic steroid class but are generally milder than those of 17-alpha-alkylated compounds. Virilization in female patients (acne, hirsutism, voice deepening, clitoral enlargement, menstrual irregularity) is the principal androgenic concern. Suppression of endogenous gonadotropin secretion (luteinizing hormone and follicle-stimulating hormone) produces dose-dependent hypothalamic-pituitary-gonadal axis suppression with consequent testicular atrophy, oligospermia, and reduced endogenous testosterone production in male users. Cardiovascular effects include unfavorable shifts in the lipoprotein profile (decreased high-density lipoprotein cholesterol, increased low-density lipoprotein cholesterol), though these shifts are generally less pronounced than those produced by 17-alpha-alkylated oral steroids. Hepatotoxicity is minimal at therapeutic doses, consistent with the absence of C17-alpha-alkylation. This monograph reviews the chemistry, synthesis, and structural pharmacology of metenolone; the androgen receptor mechanism and tissue-selective pharmacodynamics; the complete pharmacokinetic profile of both ester forms; the clinical evidence base across hematologic, catabolic, and body-composition indications; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events; and a comparative assessment of five alternative anabolic-androgenic steroids against Primobolan on five competency standards.

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  • 1,4-DMAA

    Aliphatic alkylamine sympathomimetic stimulant and putative monoamine releasing agent

    A branched-chain aliphatic amine structurally related to methylhexanamine (1,3-DMAA), identified in geranium plant material and in dietary supplements, with presumed sympathomimetic and catecholamine-releasing activity but no approved pharmaceutical application and a minimal primary pharmacological literature.

    Abstract

    1,4-Dimethylamylamine (1,4-DMAA), systematically named 5-methylhexan-2-amine, is a branched-chain aliphatic amine of the alkylamine stimulant class. It is a positional isomer of the better-characterized 1,3-dimethylamylamine (1,3-DMAA, methylhexanamine), differing in the placement of the methyl branch along the carbon backbone: in 1,3-DMAA the branch is at carbon 4 (producing 4-methylhexan-2-amine), whereas in 1,4-DMAA the branch is at carbon 5 (producing 5-methylhexan-2-amine). The compound has never been developed or marketed as a pharmaceutical agent, in contrast to 1,3-DMAA, which was introduced by Eli Lilly as an inhaled nasal decongestant (Forthane) in 1948 and voluntarily withdrawn in 1983. 1,4-DMAA came to regulatory and scientific attention through its identification in dietary supplements marketed for pre-workout stimulation and weight loss, where it was detected at doses of 21 to 94 mg per serving alongside other undeclared stimulants including 1,3-DMAA, octodrine, and 1,3-dimethylbutylamine, as reported by Cohen et al. (2018) in Clinical Toxicology. The compound has also been detected at trace concentrations (13 to 162 ng/g) in Pelargonium graveolens (geranium) plant material from the Changzhou region of China, as documented by Fleming et al. (2012), though these concentrations are insufficient to account for the milligram-scale quantities found in commercial supplement formulations. The pharmacology of 1,4-DMAA has not been independently characterized in published receptor-binding, transporter-interaction, or in vivo behavioral studies. Its mechanism of action is inferred by structural analogy to 1,3-DMAA and to the broader class of aliphatic alkylamine sympathomimetics. 1,3-DMAA has been characterized as an indirect sympathomimetic agent that competitively inhibits dopamine uptake at the human dopamine transporter (DAT) with an IC50 of approximately 29.4 micromolar (roughly 60-fold less potent than amphetamine) and that induces DAT endocytosis through cocaine- and protein kinase A-sensitive mechanisms, as reported by Bhatt et al. (2023). By structural analogy, 1,4-DMAA is presumed to function as a catecholamine releasing agent with sympathomimetic properties, producing vasoconstriction, elevated blood pressure, increased heart rate, and central nervous system stimulation, though the potency and selectivity of these effects relative to 1,3-DMAA remain unquantified. No human pharmacokinetic data specific to 1,4-DMAA have been published. The pharmacokinetic profile of 1,3-DMAA, characterized by Bloomer et al. (2013) in seven healthy men receiving a single 25 mg oral dose, provides the closest available analog: peak plasma concentration of approximately 70 ng/mL at 3.6 hours, terminal elimination half-life of 8.5 hours, oral clearance of 20 L/hr, and volume of distribution of 236 L. Whether these parameters translate to the 1,4-isomer is unknown. The safety of 1,4-DMAA in humans is unknown. The compound has not been studied in controlled clinical trials at any dose. Cardiovascular adverse events (hypertension, tachycardia, and theoretical risk of hemorrhagic stroke and sudden cardiac death) are inferred from the pharmacology of structurally related sympathomimetic amines and from case reports associated with 1,3-DMAA-containing products. The United States Food and Drug Administration considers 1,4-DMAA to be an illegal ingredient in dietary supplements and has stated that products containing it should not be consumed. The World Anti-Doping Agency includes 1,4-dimethylamylamine on the Prohibited List under category S6 (stimulants, prohibited in competition). This monograph reviews the chemistry, structural classification, inferred mechanism of action, pharmacokinetic analogy data, detection in plant material and supplements, regulatory status, adverse-event signal, sourcing and handling considerations, and a comparative assessment of five structurally or functionally related alkylamine stimulants against 1,4-DMAA on five competency standards: novelty, effect size, side-effect profile, regulatory status, and overall validation.

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  • ISRIB

    Small-molecule eIF2B activator and integrated stress response inhibitor

    A symmetrical bis-glycolamide that stabilizes the decameric eIF2B holoenzyme, counteracting phospho-eIF2alpha-mediated translational repression and reversing age-related, traumatic, and neurodegenerative cognitive deficits in preclinical models without the pancreatic toxicity of upstream PERK kinase inhibitors.

    Abstract

    ISRIB (integrated stress response inhibitor) is a cell-permeable, brain-penetrant small molecule identified by Sidrauski et al. (2013) at the University of California, San Francisco, through a phenotypic screen for compounds that render cells resistant to the translational consequences of eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation [1]. The compound blocks the integrated stress response (ISR) with an IC50 of approximately 5 nM in ATF4 reporter assays, operating downstream of all four eIF2alpha kinases (PERK, GCN2, HRI, PKR) at the level of the guanine nucleotide exchange factor eIF2B [2]. Cryo-electron microscopy studies (Tsai et al. 2018; Zyryanova et al. 2021) demonstrated that ISRIB binds at the symmetry interface of two eIF2B betagammadeltaepsilon tetrameric subcomplexes, acting as a molecular staple that promotes assembly of the catalytically active decameric holoenzyme and allosterically antagonizes the inhibitory effect of phosphorylated eIF2alpha on the nucleotide exchange reaction [3, 4]. The resulting restoration of ternary complex formation and global protein synthesis rates is partial rather than complete, reaching approximately 50 to 70 percent of unstressed control levels even at saturating compound concentrations, a feature that accounts for the favorable safety profile relative to direct PERK kinase inhibitors such as GSK2606414 that produce pancreatic exocrine destruction [5].

    Preclinical pharmacology spans multiple disease-relevant models. In cognition, ISRIB enhances spatial and fear-associated learning in wild-type mice (Sidrauski et al. 2013) [1], reverses cognitive deficits weeks after traumatic brain injury (Chou et al. 2017) [6], restores age-related memory decline and hippocampal neuronal function within days of treatment in aged mice (Krukowski et al. 2020) [7], and rescues synaptic plasticity in a mouse model of Down syndrome [8]. In neurodegeneration, ISRIB prevents neuronal loss in prion-diseased mice without pancreatic toxicity (Halliday et al. 2015) [5] and stabilizes vanishing white matter disease eIF2B mutant complexes to wild-type catalytic activity (Wong et al. 2018) [9]. Additional preclinical activity has been reported in prostate cancer [10], noise-induced cochlear synaptopathy [11], postinfarct atrial fibrillation [12], and amyotrophic lateral sclerosis models [13]. Pharmacokinetically, ISRIB exhibits good blood-brain barrier penetration and achieves brain concentrations exceeding its IC50 at intraperitoneal doses of 0.25 to 2.5 mg/kg in mice, but is limited by poor aqueous solubility requiring vehicle formulations with dimethyl sulfoxide and polyethylene glycol 400 [5, 6].

    No human clinical trials of ISRIB itself have been conducted. However, the compound served as the pharmacological prototype for two clinical-stage eIF2B activators: DNL343 (Denali Therapeutics), which completed a Phase 2/3 trial in amyotrophic lateral sclerosis (HEALEY platform trial) without meeting primary endpoints [14], and fosigotifator (Calico/AbbVie), which also failed to demonstrate significant slowing of disease progression in the same platform trial, although an exploratory high-dose arm showed signals on muscle strength preservation [15]. This monograph reviews the chemistry, stereochemistry, and synthesis of ISRIB; the molecular pharmacology of eIF2B activation and ISR inhibition; pharmacokinetic properties and formulation challenges; the preclinical evidence base across cognitive, neurodegenerative, oncologic, and inflammatory models; the clinical-translational status through derivative compounds; sourcing and quality verification for research use; reconstitution and handling; stack interactions; adverse events and safety signals; and a comparative assessment of five ISR-modulating alternatives against ISRIB on five competency standards.

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  • ITPP

    Synthetic membrane-permeant allosteric effector of hemoglobin (inositol pyrophosphate class)

    A first-in-class inositol pyrophosphate designed to cross the erythrocyte membrane, reduce hemoglobin oxygen affinity via right-shift of the oxyhemoglobin dissociation curve, and enhance regulated oxygen delivery to hypoxic tissues, with preclinical and early clinical investigation across oncology, cardiovascular, and metabolic indications.

    Abstract

    Myo-inositol trispyrophosphate (ITPP) is a synthetic pyrophosphate derivative of phytic acid that functions as a membrane-permeant allosteric effector of hemoglobin, reducing the affinity of hemoglobin for oxygen and shifting the oxyhemoglobin dissociation curve to the right, thereby enhancing the release of molecular oxygen from erythrocytes into tissues under conditions of low partial pressure of oxygen. The compound was conceived in the laboratory of Jean-Marie Lehn (Nobel Laureate in Chemistry, 1987) and Claude Nicolau in the early 2000s as a rationally designed analog of the endogenous erythrocyte effector 2,3-diphosphoglycerate (2,3-DPG), engineered to bear three cyclic pyrophosphate rings on the myo-inositol scaffold that confer net negative charge sufficient to bind the positively charged central cavity of deoxyhemoglobin while maintaining membrane permeability across the erythrocyte plasma membrane via the band 3 anion transport complex. Unlike 2,3-DPG and the structurally related phytic acid (inositol hexakisphosphate), which cannot traverse the red blood cell membrane, ITPP enters the erythrocyte intact and engages the allosteric T-state binding site of hemoglobin in situ, producing a dose-dependent rightward shift of the P50 (the partial pressure of oxygen at which hemoglobin is 50 percent saturated) without altering cooperativity or total oxygen-carrying capacity.

    The preclinical pharmacology of ITPP spans three principal therapeutic domains. In oncology, ITPP-mediated tumor reoxygenation produces downregulation of hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF), normalization of tumor vasculature through activation of the endothelial PTEN/AKT signaling axis, and potentiation of subsequent chemotherapy and radiation therapy in rodent models of pancreatic, hepatocellular, colorectal, melanoma, glioblastoma, and rhabdomyosarcoma tumors. In cardiovascular medicine, ITPP treatment in rodent models of myocardial infarction and monocrotaline-induced pulmonary hypertension has produced improved myocardial oxygenation, attenuation of adverse left and right ventricular remodeling, reduction of pulmonary hypertension-related mortality, and dose-dependent increases in maximal exercise capacity of up to 57 percent in normal mice and 63 percent in transgenic mice with severe heart failure. In metabolism, ITPP has demonstrated reduction of adipose tissue accumulation in high-fat-diet rodent models through reversal of adipose tissue hypoxia.

    The compound entered clinical development under the designation OXY111A through Normoxys, Inc. A Phase Ib dose-escalation study (NCT02528526) conducted at University Hospital Zurich enrolled 28 patients with advanced hepatopancreatobiliary malignancies and colorectal cancer liver metastases across eight dose levels (1,866 to 14,500 mg/m2 per dose), administered as nine 8-hour intravenous infusions over three weeks. The maximum tolerated dose was established at 12,390 mg/m2. The compound was well tolerated, with the principal treatment-related adverse event being asymptomatic hypercalcemia attributable to calcium chloride in the formulation rather than to the compound itself. Pharmacokinetic analysis demonstrated dose-proportional exposure with a terminal half-life of 1.3 to 3.3 hours, no systemic accumulation, and plasma clearance of 3.1 to 4.8 L/h. Morphological disease stabilization was observed in 52 percent of patients under ITPP monotherapy, and subsequent chemotherapy produced stable disease in 60 percent and partial response in 10 percent. Decreases in circulating angiogenic markers (VEGFA, angiopoietin-1, angiopoietin-2, EGF, PECAM1) were observed in a majority of patients and correlated with improved survival following chemotherapy. ITPP is prohibited in competitive sport by the World Anti-Doping Agency as a substance with potential to enhance oxygen transfer, and analytical methods for its detection in human urine and equine plasma have been developed for anti-doping enforcement.

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  • Dapoxetine

    Short-acting selective serotonin reuptake inhibitor (SSRI) with rapid-onset, rapid-elimination pharmacokinetics developed for on-demand treatment of premature ejaculation

    A naphthalene-derived phenylpropylamine SSRI originally developed at Eli Lilly as an antidepressant candidate, repositioned as the first and only oral pharmacotherapy specifically approved for on-demand treatment of premature ejaculation, distinguished from conventional SSRIs by rapid absorption, short initial half-life, and suitability for event-based rather than chronic dosing.

    Abstract

    Dapoxetine (LY 210448) is a short-acting selective serotonin reuptake inhibitor (SSRI) and the first oral pharmacotherapy specifically developed and approved for the on-demand treatment of premature ejaculation (PE) in adult men aged 18 to 64 years. Originally synthesized at Eli Lilly and Company as an antidepressant candidate in the late 1980s, the compound was shelved after failing to demonstrate sufficient efficacy in depression, subsequently licensed to Pharmaceutical Product Development (PPD) in 2003, and then advanced through Phase 3 clinical development by ALZA Corporation (a Johnson and Johnson subsidiary) for the PE indication. Dapoxetine received its first regulatory approvals in Finland and Sweden in 2009 under the trade name Priligy and has since been registered in over 60 countries across Europe, Asia, Latin America, and Oceania. The compound has not been approved by the United States Food and Drug Administration, which issued a not-approvable letter in 2005 citing the need for additional efficacy and safety data.

    The pharmacological mechanism of dapoxetine is inhibition of the serotonin transporter (SERT) at both peripheral and central sites, increasing serotonin availability at postsynaptic receptors in the ejaculatory pathway. Preclinical electrophysiology studies in anaesthetized rats demonstrated that dapoxetine inhibits the ejaculatory expulsion reflex at a supraspinal level, specifically modulating activity of lateral paragigantocellular nucleus (LPGi) neurons that project to spinal ejaculatory motor centers. The compound exhibits high selectivity for the serotonin transporter over the norepinephrine and dopamine transporters, with Ki values of approximately 1.0 nM for SERT, 66 nM for the norepinephrine transporter, and greater than 1000 nM for the dopamine transporter.

    The critical pharmacokinetic distinction of dapoxetine from conventional SSRIs (paroxetine, fluoxetine, sertraline, citalopram) is its rapid absorption and elimination profile. After oral administration, dapoxetine reaches maximum plasma concentration (Cmax) within approximately 1.0 to 1.3 hours, with an initial distribution half-life of 1.3 to 1.4 hours and a terminal elimination half-life of 18.7 to 21.9 hours. Oral bioavailability is approximately 42 percent, with substantial interindividual variability (range 15 to 76 percent) attributable to first-pass hepatic metabolism. Metabolism proceeds through CYP3A4, CYP2D6, and flavin-containing monooxygenase 1 (FMO1) pathways, producing dapoxetine N-oxide (inactive), N-desmethyldapoxetine (active), and N,N-didesmethyldapoxetine (active) as the principal circulating metabolites. Plasma protein binding exceeds 99 percent.

    Five pivotal Phase 3 randomized, double-blind, placebo-controlled trials enrolling 6,081 men across more than 25 countries established the clinical efficacy of dapoxetine at 30 mg and 60 mg on-demand doses. Integrated analysis demonstrated that mean intravaginal ejaculatory latency time (IELT) increased from a baseline of 0.9 minutes to 3.2 minutes with dapoxetine 30 mg and 3.5 minutes with dapoxetine 60 mg, compared to 1.9 minutes with placebo. Statistically significant improvements were observed across all patient-reported outcome domains including ejaculatory control, satisfaction with sexual intercourse, ejaculation-related personal distress, and interpersonal difficulty. The safety profile is consistent with the SSRI pharmacological class; the most common adverse events are nausea (8.7 to 20.1 percent), dizziness (5.8 to 10.9 percent), headache (5.6 to 8.8 percent), diarrhea (3.9 to 6.8 percent), and somnolence. A specific safety concern is vasovagal-mediated syncope, observed at rates of 0.06 percent with 30 mg and 0.23 percent with 60 mg compared to 0.05 percent with placebo. Dapoxetine is contraindicated with potent CYP3A4 inhibitors, monoamine oxidase inhibitors, other serotonergic agents, and in patients with significant cardiovascular disease or a history of syncope.

    This monograph reviews the chemistry, synthesis, and stereochemistry of dapoxetine; the serotonin transporter pharmacology and supraspinal ejaculatory reflex modulation mechanism in molecular and electrophysiological detail; the comprehensive human pharmacokinetic record including CYP2D6 and CYP3A4 metabolic polymorphism; the clinical evidence base across premature ejaculation and combination therapy with phosphodiesterase type 5 inhibitors; the reconstitution, sourcing, and quality verification considerations for laboratory work; stack-interaction implications; adverse-event signal including syncope and serotonin syndrome risk; and a comparative assessment of five alternative premature ejaculation pharmacotherapies against dapoxetine on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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  • PPAP-HCl

    Catecholaminergic activity enhancer (CAE) and dopamine transporter reuptake inhibitor derived from the phenylalkylamine/substituted amphetamine scaffold

    A selegiline-derived catecholaminergic activity enhancer that potentiates impulse-dependent dopamine and norepinephrine release in the brain without monoamine oxidase inhibition, distinguished from classical psychostimulants by a broad therapeutic dose window and absence of uncontrolled monoamine efflux.

    Abstract

    PPAP-HCl, the hydrochloride salt of (-)-(R)-1-phenyl-2-propylaminopentane, is an experimental catecholaminergic activity enhancer (CAE) compound originally synthesized by Jozsef Knoll and colleagues at Semmelweis University in Budapest in the late 1980s as a structural derivative of selegiline (L-deprenyl) designed to retain the catecholaminergic enhancer activity of the parent compound while eliminating its monoamine oxidase (MAO) inhibitory property. The compound occupies a mechanistically distinct position in the catecholaminergic pharmacology space: at low-to-moderate concentrations, PPAP potentiates the impulse-propagation-mediated (action-potential-dependent) release of dopamine and norepinephrine from catecholaminergic nerve terminals without producing the uncontrolled, impulse-independent monoamine efflux characteristic of amphetamine and methamphetamine. This “enhancer” mechanism, first formally described by Knoll in 1992 and subsequently elaborated in a series of publications through 2005, operates independently of MAO inhibition, presynaptic autoreceptor blockade, and classical reuptake inhibition, and instead potentiates the vesicular exocytotic release event coupled to the arriving action potential. Recent pharmacological characterization reported in 2025 has expanded the mechanistic profile by demonstrating that PPAP also acts as a potent dopamine transporter (DAT) reuptake inhibitor with an IC50 of 57.5 nM, a norepinephrine transporter (NET) inhibitor at 571 nM, and a weak serotonin transporter (SERT) inhibitor at 19,000 nM, placing it in a dual-mechanism category that combines enhancer activity with catecholamine reuptake inhibition. Additional evidence suggests that PPAP and related synthetic enhancer compounds may exert their catecholaminergic effects through agonism at trace amine-associated receptor 1 (TAAR1), an intracellular G-protein-coupled receptor that modulates vesicular dopamine release through protein kinase C (PKC)-mediated phosphorylation of exocytotic machinery.

    In preclinical behavioral pharmacology, PPAP facilitates learning and retention in shuttle-box avoidance paradigms, potently antagonizes tetrabenazine-induced behavioral depression, reduces immobility in the forced swimming test, and increases locomotor activity across a broad dose range (2 to 50 mg/kg in rodents) without the narrow therapeutic window and stereotypy induction that characterize amphetamine-class stimulants. The therapeutic index in animal models exceeds that of amphetamine. Structure-activity relationship studies identified the (R)-enantiomer as the pharmacologically active form, while the racemic mixture (designated MK-306) retains partial activity. PPAP served as the reference catecholaminergic activity enhancer compound in the Knoll laboratory and led directly to the development of the more potent and serotonergically active successor compound BPAP [(-)1-(benzofuran-2-yl)-2-propylaminopentane] in 1999. PPAP has been proposed as a candidate for clinical development in depression, attention deficit hyperactivity disorder (ADHD), and Alzheimer’s disease, though no human clinical trials have been completed or published. The compound is not approved by any regulatory authority for therapeutic use and is available exclusively as a research-grade preparation. This monograph reviews the chemistry, synthesis, and stereochemistry of PPAP-HCl; the dual enhancer and reuptake-inhibitor pharmacology; the preclinical behavioral and neurochemical evidence base; the comparative assessment of five catecholaminergic and monoaminergic enhancer or stimulant candidates against PPAP on five competency standards; and the sourcing, reconstitution, and handling considerations for laboratory work.

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