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IBMX
IBMX
IBMX
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IBMX
Skeletal formula of IBMX
Space-filling model of the IBMX model
Names
IUPAC name
1-Methyl-3-(2-methylpropyl)-7H-purine-2,6-dione
Other names
3-Isobutyl-1-methylxanthine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.044.767 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C10H14N4O2/c1-6(2)4-14-8-7(11-5-12-8)9(15)13(3)10(14)16/h5-6H,4H2,1-3H3,(H,11,12) checkY
    Key: APIXJSLKIYYUKG-UHFFFAOYSA-N checkY
  • InChI=1/C10H14N4O2/c1-6(2)4-14-8-7(11-5-12-8)9(15)13(3)10(14)16/h5-6H,4H2,1-3H3,(H,11,12)
    Key: APIXJSLKIYYUKG-UHFFFAOYAL
  • CC(C)Cn1c2c(c(=O)n(c1=O)C)[nH]cn2
Properties
C10H14N4O2
Molar mass 222.3 g/mol
Appearance White solid
Melting point 199 to 201 °C (390 to 394 °F; 472 to 474 K)
Solubility Soluble in ethanol, DMSO, and methanol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

IBMX (3-isobutyl-1-methylxanthine), like other methylxanthine derivatives, is both a:

  1. competitive non-selective phosphodiesterase inhibitor[1] which raises intracellular cAMP, activates PKA, inhibits TNFα[2][3] and leukotriene[4] synthesis, and reduces inflammation and innate immunity,[4] and
  2. nonselective adenosine receptor antagonist.[5]

As a phosphodiesterase inhibitor, IBMX has IC50 = 2–50 μM[6] and does not inhibit PDE8 or PDE9.[7]

References

[edit]
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IBMX

View on Grokipedia
from Grokipedia
IBMX (3-isobutyl-1-methyl) is a synthetic derivative that serves as a potent and non-selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of intracellular second messengers () and (). By blocking PDE activity, IBMX elevates and levels in cells, thereby activating downstream signaling pathways such as () and influencing processes like hormone responsiveness and modulation. Chemically, it has the molecular formula C₁₀H₁₄N₄O₂, a of 222.24 g/mol, and appears as a white crystalline solid with a of 199–201 °C; it is soluble in (DMSO) and but sparingly soluble in water. As a research tool, is extensively utilized in and to mimic or enhance cAMP/cGMP-mediated effects, with typical concentrations ranging from 10 μM to 1 mM in experimental settings. Its inhibitory potency varies across PDE isoforms, with IC₅₀ values of approximately 6.5 μM for PDE3, 26.3 μM for PDE4, and 31.7 μM for PDE5, making it particularly useful for broad-spectrum studies rather than isoform-specific targeting. Beyond PDE inhibition, IBMX functions as an at receptors (A1 and A2 subtypes), which contributes to its role in suppressing release and modulating cellular responses in models of neuroendocrine function and . In vitro applications include promoting melanogenesis in cells, facilitating neural differentiation, inhibiting vascular , and enhancing maturation in . While not approved for clinical use due to its non-specificity and potential toxicity, IBMX remains a cornerstone reagent for elucidating signaling in diverse physiological and pathological contexts.

Chemical Characteristics

Molecular Structure and Nomenclature

IBMX, chemically known as 3-isobutyl-1-methylxanthine, is a synthetic derivative of with the molecular formula C10H14N4O2C_{10}H_{14}N_4O_2. Its systematic IUPAC name is 1-methyl-3-(2-methylpropyl)-7H-purine-2,6-dione, reflecting the purine ring system with specific alkyl substitutions. Common synonyms include IBMX and 3-isobutyl-1-methyl-7H-purine-2,6-dione, which emphasize its xanthine backbone and substituent positions. The molecular structure of IBMX is based on the core, a bicyclic system consisting of a ring fused to an ring, with oxo groups at positions 2 and 6 of the purine numbering. This core features a (−CH3-CH_3) attached to the at position 1 and an isobutyl group (−CH2CH(CH3)2-CH_2CH(CH_3)_2) at the at position 3. Positions 7 and 8 remain unsubstituted, with a at N7, contributing to its tautomerism as the 7H form. The isobutyl chain at N3 provides steric bulk compared to simpler alkyl groups, influencing its chemical behavior. IBMX belongs to the class of methylxanthines and is structurally analogous to (1,3-dimethylxanthine), differing primarily by the replacement of the N3-methyl group with an isobutyl substituent. This modification enhances its potency relative to theophylline in certain biochemical interactions.

Physical and Chemical Properties

IBMX appears as a to off-white crystalline . Its is 222.24 g/mol. The compound has a of 199–201 °C. IBMX exhibits good solubility in organic solvents such as (DMSO), where it dissolves at concentrations up to 1 M with gentle warming, and , with solubility around 10 mg/mL. It is sparingly soluble in , approximately 0.3 mg/mL in hot . The pKa value is approximately 8.61, reflecting weak basicity attributable to the nitrogen atoms. The compound is chemically stable under neutral conditions and remains viable for up to 2 years when stored as supplied at -20 °C; it is non-volatile as a . Spectroscopic reveals a UV absorption maximum at 270 nm and characteristic IR absorption peaks for the carbonyl groups in the 1650–1700 cm⁻¹ range.

Pharmacology

Mechanism of Action

IBMX functions as a competitive, non-selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs), targeting multiple isoforms including PDE1–PDE7, PDE10, and PDE11, with particular potency against PDE3, PDE4, and PDE5 (IC50 values of approximately 6–32 μM for these isoforms). At the molecular level, IBMX binds directly to the catalytic site of PDEs, occupying a subpocket within the active site and forming key interactions that block substrate access. This binding involves hydrophobic stacking of the xanthine ring against phenylalanine residues (e.g., Phe-372 in PDE4D2 or Phe-820 in PDE5A1), hydrogen bonding between the purine ring and a conserved glutamine (e.g., Gln-369 in PDE4D2 or Gln-817 in PDE5A1), and additional hydrophobic contacts via the isobutyl substituent. By sterically hindering the enzyme's active site, IBMX prevents the hydrolysis of phosphodiester bonds in both cAMP and cGMP, thereby elevating their intracellular concentrations. The inhibitory effect follows competitive kinetics, reducing the rate of PDE-mediated hydrolysis according to the modified Michaelis-Menten equation: v=Vmax⁡[S]Km(1+[I]Ki)+[S]v = \frac{V_{\max} [S]}{K_m \left(1 + \frac{[I]}{K_i}\right) + [S]} where vv is the initial velocity, [S][S] is the substrate (cAMP or cGMP) concentration, Vmax⁡V_{\max} is the maximum velocity, KmK_m is the Michaelis constant, [I][I] is the IBMX concentration, and KiK_i (or approximate IC50) ranges from 10–50 μM across most PDE isoforms. In comparison to the related xanthine analog (IC50 ≈ 50–100 μM), IBMX exhibits greater potency as a PDE inhibitor, attributed to the 3-isobutyl group, which provides enhanced hydrophobic interactions with residues in the PDE subpocket beyond those afforded by theophylline's 3-methyl group. A secondary consequence of PDE inhibition by IBMX is the indirect activation of (PKA) through sustained elevation of cAMP levels, without any evidence of direct agonism at PKA or other enzymes.

Pharmacodynamics and Biological Effects

IBMX acts as a non-selective inhibitor of phosphodiesterases (PDEs), leading to elevated intracellular levels of (cAMP) and (cGMP) by preventing their . This accumulation activates (PKA) through cAMP binding, resulting in downstream events that modulate various cellular processes. In vitro studies demonstrate that IBMX at concentrations of 0.5 mM increases cAMP levels approximately 3-fold in insulin-producing beta TC1 cells, while effects on cGMP vary by tissue but contribute similarly to signaling amplification. In addition to PDE inhibition, IBMX acts as a non-selective at receptors (A1 and A2 subtypes), with approximate Ki values of 20–50 μM, which contributes to suppression of -mediated responses and modulation of release. Tissue-specific biological effects of IBMX arise from these elevations, influencing diverse physiological responses. In adipocytes, IBMX promotes by enhancing cAMP-mediated PKA activation, which phosphorylates and activates hormone-sensitive (HSL), facilitating breakdown and free release. In melanocytes, particularly in B16 cell models, IBMX stimulates melanogenesis via increased cAMP levels that upregulate the (MITF), driving expression of and other melanogenic enzymes. In smooth muscle cells, IBMX elevates cGMP, activating protein kinase G (PKG) to promote relaxation through reduced intracellular calcium and myosin light chain . Cardiovascular effects of IBMX include mild positive inotropy and chronotropy in cardiac myocytes, attributed to cAMP elevation that enhances PKA-dependent of L-type calcium channels and phospholamban, increasing contractility and . Neurologically, IBMX inhibits tumor necrosis factor-α (TNF-α) synthesis in inflammatory cells like adipocytes by sustaining cAMP levels that suppress activation. It also reduces synthesis through PKA-mediated of 5-lipoxygenase (5-LO), attenuating inflammatory production. Additionally, IBMX modulates voltage-gated calcium currents in neurons via cAMP-dependent mechanisms. IBMX exhibits dose-dependent effects, typically effective at 10–500 μM to achieve PDE saturation and cyclic nucleotide accumulation without excessive off-target actions, though higher doses risk non-specific antagonism and .

Research Applications

In Cell Signaling and Differentiation

IBMX plays a crucial role in experimental protocols for investigating cAMP-mediated signaling pathways, where it is frequently combined with to mimic or amplify the effects of G-protein coupled receptor (GPCR) activation on . By inhibiting activity, IBMX prevents cAMP degradation, thereby elevating intracellular cAMP levels and enabling researchers to study downstream signaling events such as activation independent of ligand-receptor interactions. In cell differentiation studies, IBMX is a key component of induction cocktails for , particularly in preadipocyte models like 3T3-L1 cells. Typically administered at 0.5 mM alongside dexamethasone and insulin for 2–3 days, IBMX promotes the conversion of preadipocytes to mature adipocytes by elevating cAMP levels, which in turn upregulates (PPARγ), a master regulator of adipogenic gene expression. This protocol enhances lipid accumulation and expression of adipocyte markers such as fatty acid-binding protein 4, providing a standardized method to dissect the molecular mechanisms of cell development. IBMX is widely employed in oocyte maturation research to inhibit spontaneous meiotic resumption in cumulus-enclosed s, maintaining elevated cAMP levels that suppress (CDK1) activation and preserve I arrest. In porcine and murine models, IBMX treatment (often at 0.1–1 mM) during culture significantly reduces germinal vesicle breakdown rates by blocking phosphodiesterase-mediated cAMP hydrolysis, allowing controlled studies of hormonal triggers for meiotic progression. This application highlights IBMX's utility in for synchronizing oocyte development and improving assisted reproduction techniques. In research, IBMX enhances differentiation of mesenchymal s (MSCs) toward osteogenic and adipogenic lineages when combined with agents like or dexamethasone. For adipogenic induction, IBMX (typically 0.5 mM) in MSC culture media boosts cAMP signaling to initiate formation and PPARγ expression, while in osteogenic protocols, it modulates early repression (e.g., ) but promotes late-stage mineralization and production in 3D spheroid cultures of adipose-derived MSCs. These effects underscore IBMX's role in fine-tuning lineage commitment for applications. IBMX also facilitates the differentiation of neural progenitor cells (NPCs) by elevating cAMP levels, which activates and modulates voltage-gated calcium channels, promoting neuronal maturation. In studies using NPCs from the , IBMX treatment (e.g., 0.5 mM) enhances the expression of neuronal markers such as β-III tubulin and increases the proportion of cells exhibiting neuronal electrophysiological properties. For melanocyte studies, IBMX serves as a positive control in assays measuring activity and production, stimulating melanogenesis in cell lines such as B16F10 cells at concentrations of 0.2–1 mM. Co-treatment with α-melanocyte-stimulating hormone elevates cAMP to increase expression and intracellular content up to 2.5-fold, providing a benchmark for evaluating potential skin-whitening compounds or pigmentation regulators. This standardized use facilitates of melanogenic pathways in dermatological research.

In Biochemical and Physiological Studies

IBMX serves as a standard non-selective (PDE) inhibitor in biochemical assays designed to measure PDE activity, particularly in colorimetric and fluorescence-based kits that quantify basal PDE rates by preventing degradation. At concentrations around 100 μM, IBMX effectively blocks the activity of multiple PDE isoforms (e.g., PDE1–5, PDE7, and PDE11), often achieving greater than 90% inhibition in targeted assays, thereby allowing accurate assessment of and inhibitor potency. In studies of and hormone signaling, IBMX potentiates β-adrenergic receptor-mediated responses in isolated fat cells by elevating intracellular cAMP levels. For instance, at 0.05 mM, IBMX enhances isoproterenol-stimulated release, a marker of , and demonstrates approximately 20-fold greater potency compared to in stimulating this process. This application highlights IBMX's role in elucidating cAMP-dependent pathways in metabolism, briefly referencing its amplification of lipolytic effects via cAMP accumulation as noted in broader pharmacodynamic contexts. IBMX is employed in inflammatory models to investigate cytokine regulation, particularly in ex vivo macrophage cultures where it reduces production of pro-inflammatory cytokines such as TNF-α. By inhibiting PDEs and sustaining cAMP elevation, IBMX suppresses LPS-induced TNF-α release, providing insights into signaling cascades. In cardiovascular , IBMX facilitates the study of cAMP-dependent contractility in perfused heart models, where it enhances β-adrenergic responses and modulates force generation; additionally, in neuronal cultures, it influences activity, altering calcium influx and synaptic transmission. IBMX also inhibits migration of vascular cells (VSMCs) in response to stimuli like thrombospondin-1 by elevating cAMP levels; for example, co-treatment with at 10 μM and IBMX at 100 μM abolishes induced migration in rat aortic VSMCs, aiding studies of vascular remodeling and restenosis prevention. For physiological investigations, IBMX is administered intraperitoneally to rats at doses of 10–50 mg/kg to elevate brain cAMP levels, enabling exploration of noradrenergic systems through increased hydroxylation and norepinephrine turnover. These models have been instrumental in probing mechanisms of glutamate and central dynamics without direct structural alterations.

Synthesis and Production

Laboratory Synthesis Methods

IBMX is typically synthesized in laboratory settings from 9-substituted 1-methylxanthine through selective N3 . The process involves treating 9-substituted 1-methylxanthine with isobutyl in the presence of a base, such as , in (DMF) as the . This step exploits the higher acidity of the N3 proton in xanthines, which facilitates preferential at that position over N7, with the 9-substituent being eliminated during the reaction. The reaction is conducted under conditions at temperatures between 0 and 25 °C to minimize side products. Following the , the product is purified by recrystallization from a suitable , yielding the desired IBMX in good efficiency.

Commercial Availability

IBMX is commercially available from several specialized chemical suppliers primarily for research purposes, including , Tocris Bioscience, and Cayman Chemical. These suppliers offer IBMX as a white to off-white powder with high purity levels, typically ≥98% as determined by (HPLC). The compound is commonly supplied in vials ranging from 50 mg to 1 g, allowing flexibility for laboratory-scale experiments. Pricing varies by supplier, quantity, and region but generally falls in the range of $50–$200 per gram for standard research-grade material. For instance, Cayman Chemical lists 1 g at $215, while smaller quantities like 50 mg from Tocris Bioscience are priced at $113. Quality standards for commercially supplied IBMX emphasize for research use only, with suppliers providing certificates of that verify purity and include data on (PDE) inhibition potency, such as IC₅₀ values below 50 μM for multiple PDE isoforms. These documents ensure batch-to-batch consistency and compliance with reagent-grade specifications. To maintain stability, storage is recommended at -20 °C in a to prevent degradation from moisture exposure. IBMX is supplied strictly under chemical classifications and is not intended for or veterinary therapeutic use.

Safety and

Adverse Effects and Toxicity

IBMX demonstrates in experimental animal models, with an intraperitoneal LD50 of 44 mg/kg reported in mice. At high doses, it elicits stimulation, , and tremors, effects analogous to those observed in overdose due to shared methylxanthine pharmacology. In embryos, IBMX exhibits embryotoxicity at concentrations in the mg/L range; exposure leads to dose-dependent mortality, pericardial and edema, disrupted blood circulation, and cardiac structural and functional abnormalities, including elevated heart rates and malformed atria and ventricles. These cellular toxicities are linked to excessive cAMP accumulation from inhibition, potentially overwhelming cellular signaling pathways. Prolonged exposure to IBMX sensitizes cardiac myocytes to anoxia, reducing cell viability during oxygen deprivation by lowering the ATP/ADP ratio, a mechanism independent of L-type calcium channels or preconditioning effects. While chronic IBMX treatment can reverse agonist-induced desensitization of alpha-1-adrenergic receptors by sustaining cAMP levels, it carries a of hyperstimulation in responsive tissues due to persistent elevation of intracellular cAMP. , concentrations exceeding 1 mM induce non-specific in cell cultures, such as mesenchymal stem cells, where 5 mM exposure causes significant cell loss within hours, attributed to disrupted cellular . Drug interactions with IBMX amplify risks associated with other cAMP-elevating agents; co-administration with β-agonists potentiates cardiovascular and CNS adverse effects through synergistic inhibition and activation. Similarly, combination with other methylxanthines like increases toxicity via additive inhibition of pathways, including , potentially leading to elevated plasma levels and enhanced tachycardic or stimulatory responses.

Regulatory Status

IBMX is not approved by the U.S. (FDA) or the (EMA) for any clinical or therapeutic use and is exclusively classified as a under CAS number 28822-58-4. Commercial suppliers label it strictly for laboratory research purposes, prohibiting human or veterinary applications. In the United States, IBMX is treated as a DEA-exempt chemical, absent from the schedules of controlled substances maintained by the (DEA). Its handling in research settings typically requires approval from institutional biosafety committees to ensure compliance with protocols. Internationally, IBMX remains available within the under the REACH regulation for non-commercial research activities, with no specific registration number indicating low-volume use below mandatory thresholds; it is not scheduled under conventions on psychotropic substances, unlike certain other derivatives. Safety data sheets indicate potential toxicity to aquatic organisms and recommend avoiding release into drains or waterways to mitigate ecological risks, though data on environmental persistence and degradability are limited. Historically, was developed in the as one of the earliest pan-phosphodiesterase inhibitors synthesized. As an off-patent compound, its generic synthesis faces no active barriers, facilitating widespread research availability.

References

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