AICAR Research Guide — AMPK Activator, ZMP/AMP Mimic Mechanism & Exercise Biology Data (2026)
- AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; also AICA riboside; INN: acadesine; CAS: 2627-69-2; MW: ~338.31 Da) is a synthetic nucleoside analog that functions as the most widely used pharmacological activator of AMP-activated protein kinase (AMPK) in intact cells and in vivo. AICAR itself is not the active form: it is cell-permeable and is phosphorylated intracellularly by adenosine kinase to AICAR monophosphate (ZMP), an AMP analog. ZMP allosterically activates AMPK by mimicking the high-AMP:ATP ratio produced by energy depletion during exercise. YPB offers research-grade AICAR as YPB.250 (Research Use Only).
- Mechanism: ZMP allosterically activates AMPK — the master cellular energy sensor — mimicking the low-energy state produced by exercise. AMPK activation drives a coordinated metabolic shift: (1) phosphorylates and inactivates acetyl-CoA carboxylase (ACC) → decreases malonyl-CoA → relieves CPT1 inhibition → increases fatty acid transport into mitochondria for β-oxidation; (2) stimulates GLUT4 translocation to sarcolemma → increases insulin-independent glucose uptake in skeletal muscle; (3) activates SIRT1 → deacetylates PGC-1α → drives mitochondrial biogenesis gene program; (4) inhibits ACC2 and HMGCR → reduces biosynthetic energy consumption. Landmark paper: Merrill et al. (1997) Am J Physiol (PMID: 9435525).
- Critical caveat — AMPK-independent effects: ZMP is an AICAR ribotide (a purine precursor intermediate in de novo purine synthesis) and has documented AMPK-independent effects including activation of the purine nucleotide cycle, direct anti-proliferative effects in some cancer cell lines, and fructose-1,6-bisphosphatase inhibition. A published systematic review (PMC8147799) documents that many AICAR effects attributed to AMPK may involve these parallel pathways. AMPK knockout/knockdown controls are required to assign specific effects to AMPK vs. AMPK-independent ZMP biology.
- WADA prohibited: S4 (Hormone and Metabolic Modulators). Not approved by FDA for any indication. Research Use Only (RUO). Updated April 2026.
What Is AICAR and Why Is It the Foundational AMPK Research Tool?
Landmark Merrill 1997 Paper
Upstream Exercise Cascade Probe
AICAR (CAS: 2627-69-2; MW: ~338.31 Da) is a nucleoside analog that has served as the primary pharmacological tool for studying AMPK biology for nearly three decades. Updated April 2026. Its use as an AMPK activator was established by Merrill, Hardie, Winder, and colleagues (1997), who demonstrated that AICAR perfusion activates AMPK in skeletal muscle, inactivates acetyl-CoA carboxylase, decreases malonyl-CoA, and increases fatty acid oxidation and glucose uptake (PMID: 9435525). This foundational paper launched AICAR as the standard pharmacological AMPK-activating tool used in hundreds of subsequent exercise biology, metabolism, and aging studies.
AICAR occupies the same exercise-mimetic research space as MOTS-c and SLU-PP-332 but at a mechanistically distinct level. Where SLU-PP-332 activates ERRα downstream of the full AMPK cascade, AICAR activates AMPK upstream — it is the most direct pharmacological mimic of the “exercise stress signal” itself. This positional distinction makes AICAR the tool of choice when researchers want to study what AMPK activation does upstream, while SLU-PP-332 allows isolation of ERRα-specific transcriptional effects downstream. Together they define both ends of the exercise adaptation signaling cascade.
Key Characteristics
| Parameter | Value |
|---|---|
| Full Name | 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; INN: acadesine; AICA riboside |
| CAS Number | 2627-69-2 |
| Molecular Weight | ~338.31 Da |
| Classification | Synthetic nucleoside analog (not a peptide); purine metabolism intermediate analog; cell-permeable AMPK activator |
| Active Form | AICAR is the procompound; intracellularly phosphorylated by adenosine kinase to ZMP (AICAR monophosphate; 5-aminoimidazole-4-carboxamide ribonucleotide) — ZMP is the active AMPK-activating species and AMP mimic |
| Primary Target | AMPK (AMP-activated protein kinase; heterotrimeric serine/threonine kinase; α, β, γ subunits); ZMP activates AMPK allosterically via the γ subunit AMP-binding site (same site activated by physiological AMP during energy depletion) |
| Key Downstream Effects | ACC phosphorylation/inactivation → malonyl-CoA decrease → CPT1 derepression → fatty acid β-oxidation increase; GLUT4 translocation → glucose uptake increase; SIRT1 activation → PGC-1α deacetylation → mitochondrial biogenesis; mTORC1 inhibition → protein synthesis reduction |
| Landmark Publication | Merrill et al. (1997) Am J Physiol Endocrinol Metab 273:E1107–E1112. PMID: 9435525. |
| AMPK-Independent Caveat | ZMP has documented AMPK-independent effects: purine synthesis pathway activation, fructose-1,6-bisphosphatase inhibition, direct anti-proliferative effects in some cancer lines. AMPK KO/KD controls required to attribute specific effects to AMPK. |
| Half-Life | Short (nucleoside; rapidly dephosphorylated/metabolized); in research protocols typical dosing is acute (single dose or multi-hour incubation) rather than sustained |
| FDA Status | Not research-grade. Acadesine reached Phase 3 clinical trials for cardioprotection during cardiac surgery (GUARDIAN trial, 2002) but did not meet primary endpoints. Research Use Only (RUO). |
| WADA Status | Prohibited — S4 Hormone and Metabolic Modulators (exercise mimetics/metabolic modulators category), WADA 2025 |
| Storage | Lyophilized: −20°C. Reconstituted: 2–8°C, use within 7 days. Water-soluble (nucleoside; contrast with SLU-PP-332 which requires DMSO); dissolve directly in PBS or culture medium |
How Does AICAR Work? The ZMP/AMPK/ACC/CPT1 Signaling Cascade
AICAR’s mechanism involves a two-step activation process: first, conversion to the active form inside the cell; second, allosteric AMPK activation driving a coordinated metabolic reprogramming cascade.
Step 1: Intracellular Conversion to ZMP
AICAR is taken up by cells via nucleoside transporters and is phosphorylated by adenosine kinase to produce ZMP (AICAR monophosphate; 5-aminoimidazole-4-carboxamide ribonucleotide). ZMP is structurally analogous to AMP (adenosine monophosphate) and binds the γ subunit AMP-binding sites of AMPK. In normal physiology, AMPK is activated when the AMP:ATP ratio rises during energy-demanding exercise or metabolic stress. ZMP mimics this signal without requiring actual energy depletion, producing AMPK activation in cells that are not undergoing genuine metabolic stress.
Step 2: AMPK Activation → ACC → Malonyl-CoA → CPT1 → Fatty Acid Oxidation
The primary well-characterized metabolic consequence of AICAR-induced AMPK activation in skeletal muscle is the ACC/malonyl-CoA/CPT1 axis. AMPK phosphorylates and inactivates acetyl-CoA carboxylase (ACC), the enzyme that converts acetyl-CoA to malonyl-CoA. Malonyl-CoA is a potent inhibitor of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme for fatty acid import into the mitochondrial matrix. When AICAR activates AMPK → inactivates ACC → decreases malonyl-CoA → derepresses CPT1, fatty acids can enter the mitochondria and undergo β-oxidation at markedly increased rates. Merrill et al. (1997) documented a 2.8-fold increase in fatty acid oxidation in rat hindlimb perfused with 2 mM AICAR, alongside ACC inactivation and malonyl-CoA decrease.
GLUT4 Translocation and Insulin-Independent Glucose Uptake
AICAR-induced AMPK activation also promotes GLUT4 vesicle translocation to the sarcolemma, increasing glucose uptake in skeletal muscle through an insulin-independent mechanism. This glucose uptake effect is pathway-convergent with exercise-stimulated glucose uptake and has been the basis for substantial research into AICAR as a potential metabolic disease tool (type 2 diabetes models). Importantly, published studies using AMPK α2 knockout mice confirmed that the glucose uptake effect is AMPK-dependent, while noting that the downstream mechanistic steps between AMPK activation and GLUT4 translocation diverge from those of exercise-induced glucose transport at points downstream of AMPK.
What Research Applications Has AICAR Been Studied For?
Exercise Biology and Metabolic Adaptation
AICAR is the foundational pharmacological AMPK activator for exercise biology research. Published studies have used AICAR to study AMPK’s role in: fatty acid oxidation rate regulation in skeletal muscle (ACC/malonyl-CoA axis); GLUT4 translocation and insulin-independent glucose uptake; PGC-1α-driven mitochondrial biogenesis; fiber type remodeling (toward oxidative phenotype with chronic treatment); and interaction between AICAR-induced AMPK activation and contraction-induced AMPK activation. Because AICAR activates AMPK without mechanical contraction, it allows dissection of the AMPK-dependent component of exercise adaptation from the mechanical-stress-dependent component.
Type 2 Diabetes and Insulin Resistance Research
AICAR’s ability to drive insulin-independent GLUT4 translocation and improve glucose disposal has made it a widely used tool in insulin resistance and type 2 diabetes models. Studies in diabetic and insulin-resistant animal models documented improved glycogen repletion, glucose tolerance, and insulin sensitivity following AICAR administration. These data supported the concept of AMPK as a therapeutic target for metabolic disease.
Cardioprotection Research
Academic AICAR (acadesine) reached clinical trials for cardioprotection: the GUARDIAN Phase 3 trial (2002) evaluated IV acadesine for reduction of myocardial ischemia-reperfusion injury during coronary artery bypass surgery. The primary endpoint (combined cardiac death, MI, and stroke) was not met in the overall population, though pre-specified subgroup analyses suggested potential benefit in higher-risk research subjects. This remains the most advanced clinical program for AICAR to date.
Cancer Biology Research (AMPK-Independent Effects)
ZMP’s direct anti-proliferative effects in certain cancer cell lines (particularly lymphoid malignancies) have been studied separately from the AMPK/metabolic axis. AICAR/acadesine has been investigated as an anti-leukemia agent in B-cell chronic lymphocytic leukemia (B-CLL) models through AMPK-independent apoptosis induction. These effects illustrate the ZMP-independent biology dimension.
What Does the Research Data Show?
| Study / Application | Model | Key Finding & Notes | Year |
|---|---|---|---|
| Merrill et al. — Foundational AMPK characterization | Ex vivo rat hindlimb perfusion | AICAR (0.5–2.0 mM) activated AMPK in skeletal muscle, inactivated ACC, decreased malonyl-CoA, produced 2.8-fold increase in fatty acid oxidation and significant glucose uptake increase. Foundational paper establishing AICAR as AMPK-activating tool. (Am J Physiol, 1997 — PMID: 9435525) | 1997 |
| Insulin resistance / T2DM models | In vivo (STZ-diabetic rats; insulin-resistant animal models; multiple groups) | AICAR improved glycogen storage, glucose tolerance, and insulin sensitivity in multiple diabetic and insulin-resistant models. Confirmed AMPK-dependent glucose uptake via GLUT4 translocation. AMPK α2 KO mice showed abolished effect, confirming AMPK dependency for glucose uptake. | Various |
| GUARDIAN Phase 3 Trial — Cardioprotection | Randomized, double-blind, Phase 3 / coronary artery bypass surgery research subjects | IV acadesine did not meet primary composite cardiac endpoint (cardiac death, MI, stroke) in the overall population. Pre-specified subgroup analyses suggested potential benefit in higher-risk research subjects. Not research-grade. This remains the only published Phase 3 trial for AICAR/acadesine. | 2002 |
| AMPK-independent ZMP effects (systematic review) | Multiple in vitro and in vivo models; literature review | Published systematic review (Herzig & Shaw, Nat Rev Mol Cell Biol, 2018; PMC8147799 comprehensive review) documented AMPK-independent ZMP effects including: fructose-1,6-bisphosphatase inhibition, purine synthesis activation, direct cancer cell anti-proliferative effects. AMPK KO/KD controls strongly recommended in AICAR research protocols. | 2018–2021 |
How Does AICAR Compare to Other Exercise Biology Research Compounds?
| Parameter | AICAR | SLU-PP-332 | MOTS-c | 5-Amino-1MQ |
|---|---|---|---|---|
| Classification | Nucleoside analog (small molecule; procompound → ZMP active form) | Small molecule; pan-ERRα/β/γ agonist; nuclear receptor | Mitochondria-derived peptide (16 AA) | Small molecule; NNMT inhibitor; NAD+ salvage pathway |
| Primary Target | AMPK (via ZMP AMP mimic; γ subunit allosteric activation) | ERRα/β/γ (orphan nuclear receptors; transcriptional) | AMPK (distinct pathway; mitochondrial FOXO1 signaling) | NNMT (nicotinamide N-methyltransferase); NAD+ metabolism |
| Cascade Position | Upstream: AMPK activation → SIRT1 → PGC-1α → ERRα | Downstream: directly activates ERRα; bypasses AMPK/SIRT1 | Upstream (distinct entry): mitochondrial AMPK/FOXO1 | Parallel: NAD+ elevation → sirtuin activation; distinct from AMPK axis |
| Key Metabolic Effects | Fatty acid β-oxidation (ACC/malonyl-CoA/CPT1); insulin-independent glucose uptake (GLUT4); mitochondrial biogenesis (via SIRT1/PGC-1α) | Type IIa fiber remodeling; fatty acid oxidation gene program; mitochondrial biogenesis; energy expenditure increase | Mitochondrial AMPK activation; exercise gene program; insulin sensitization | NNMT inhibition → NAD+ ↑ → SIRT1/SIRT3 activation → metabolic reprogramming |
| AMPK-Independent Effects | Yes — well-documented; ZMP affects purine synthesis, FBPase, cancer cell proliferation. AMPK KO controls required. | Possible off-target nuclear receptor effects; ERRα KO controls recommended | Primarily AMPK-dependent; distinct from ZMP pathway | NNMT-specific; limited off-target documentation |
| WADA Status | Prohibited (S4 Hormone and Metabolic Modulators) | Under monitoring (exercise mimetics) | Not listed 2025 | Not listed 2025 |
| YPB SKU | YPB.250 — see product | YPB.243 — see guide | YPB.227 — see guide | YPB.244 — see guide |
AICAR and SLU-PP-332 are the most directly complementary pairing in the exercise biology catalog. AICAR activates AMPK upstream (see the SLU-PP-332 Research Guide for the downstream ERRα tool); MOTS-c activates AMPK through a distinct mitochondrial peptide entry point (see the MOTS-c Research Guide); 5-Amino-1MQ addresses the NAD+/sirtuin axis in parallel (see the 5-Amino-1MQ Research Guide). Together these four compounds cover AMPK/ZMP, ERRα transcription, mitochondrial peptide AMPK, and NAD+/sirtuin metabolism — four distinct nodes of the cellular energy and exercise adaptation network.
What Should Researchers Know About AICAR Handling?
Water Solubility Advantage
Unlike SLU-PP-332, AICAR has good aqueous solubility (nucleoside). It can be dissolved directly in PBS, HEPES-buffered saline, or culture medium without DMSO vehicle. This simplifies cell culture protocol design and avoids DMSO cytotoxicity concerns. Standard working concentrations in cell-based AMPK activation studies: 0.5–2.0 mM (skeletal muscle); note that effective concentrations are in the millimolar range (significantly higher than receptor-ligand compounds like SLU-PP-332 at nanomolar concentrations) because ZMP is produced intracellularly at only a fraction of the extracellular AICAR concentration.
Time Course Considerations
AICAR/ZMP-mediated AMPK activation is relatively rapid (AMPK phosphorylation detectable within 15–30 minutes of AICAR addition). Downstream effects (PGC-1α upregulation, mitochondrial biogenesis gene induction) require longer time courses (hours to days). Protocols should distinguish acute AMPK activation endpoints (30–60 minutes; phospho-ACC, phospho-AMPK) from chronic metabolic adaptation endpoints (hours to days; gene expression, mitochondrial content, fiber type markers).
Storage
Lyophilized: −20°C for up to 24 months. Reconstituted aqueous solution: 2–8°C, use within 7 days. Unlike lipidated peptides or DMSO-soluble small molecules, AICAR reconstituted solutions do not require special low-protein-binding containers. All YPB AICAR batches include lot-traceable COA documentation through the COA Library.
Key Research Findings
- Foundational AMPK research tool (Merrill et al. 1997, PMID: 9435525): First established AICAR as AMPK activator in skeletal muscle via ZMP AMP mimic; 2.8-fold fatty acid oxidation increase; glucose uptake increase; ACC inactivation/malonyl-CoA decrease documented.
- Procompound mechanism (AICAR → ZMP): AICAR is cell-permeable; phosphorylated by adenosine kinase to ZMP; ZMP binds AMPK γ subunit AMP-binding sites; allosteric AMPK activation without genuine energy depletion.
- ACC/malonyl-CoA/CPT1 axis is the primary fatty acid oxidation mechanism: AMPK → phospho-ACC → malonyl-CoA decrease → CPT1 derepression → fatty acid mitochondrial import → β-oxidation. This is the canonical AICAR research endpoint for fatty acid metabolism studies.
- GLUT4 translocation and insulin-independent glucose uptake: AMPK α2 KO abolishes AICAR-induced glucose uptake; confirmed AMPK-dependent. Mechanistically convergent with exercise-stimulated glucose uptake but with distinct downstream steps.
- AMPK-independent ZMP effects are real and documented: Purine synthesis pathway activation, fructose-1,6-bisphosphatase inhibition, direct cancer cell anti-proliferative effects. AMPK KO/KD controls are required to attribute effects to AMPK vs. ZMP-independent pathways.
- Upstream of SLU-PP-332 in the exercise cascade: AICAR activates AMPK → SIRT1 → PGC-1α → ERRα; SLU-PP-332 activates ERRα directly. Parallel use enables cascade dissection.
- Phase 3 clinical trial (GUARDIAN 2002) — primary endpoint not met: IV acadesine for coronary bypass cardioprotection; most advanced clinical program; negative primary endpoint. Not research-grade.
- WADA S4 Prohibited (Hormone and Metabolic Modulators): Exercise mimetics/metabolic modulators; reflects recognized AMPK/exercise-adaptation-activating activity.
Browse the Full Research Catalog
Market Demand and Research Interest
| Demand Indicator | AICAR Data Point |
|---|---|
| PubMed publications | 3,500+ (AICAR / acadesine / AICA riboside) |
| Foundational role | Standard pharmacological AMPK activator since 1997; used across exercise biology, metabolism, diabetes, cancer, cardioprotection research |
| Unique catalog position | Only AMPK ZMP-mechanism activator; upstream complement to SLU-PP-332; water-soluble (no DMSO required) |
| Research audience | Metabolic disease; exercise physiology; diabetes biology; mitochondrial research; aging biology; cancer metabolism |
| WADA S4 Prohibited | Reflects recognized exercise mimetic activity; consistent with research interest from anti-doping and sports science communities |
| AMPK field growth | AMPK remains one of the most intensively studied kinases in metabolic biology; new AMPK activators and downstream targets continue to be published at high rate |
| Keyword difficulty range | Low-medium (KD <20) |
How Can Researchers Offer AICAR Under Their Own Brand?
Wholesale Pricing & Margin Analysis
| SKU | Compound | Premier ($497/mo) | Core ($297/mo) | Suggested MSRP | Premier Margin |
|---|---|---|---|---|---|
| YPB.250 (RUO) | AICAR (Acadesine; 5-aminoimidazole-4-carboxamide riboside) | TBC Premier | TBC Core | TBC | TBC at Premier tier |
Contact the YPB team for confirmed Premier and Core tier pricing. Use the YPB Profit Calculator to model projected revenue. White-label brands offering AICAR (YPB.250), SLU-PP-332 (YPB.243), and MOTS-c (YPB.227) create the most mechanistically complete exercise-adaptation and metabolic research toolkit available: AMPK upstream activation (AICAR/ZMP) + ERRα downstream transcription (SLU-PP-332) + mitochondrial AMPK peptide pathway (MOTS-c). Download the full catalog for all exercise biology category pricing.
Methodology & Data Sources
Methodology & Data Sources
Scientific literature: PubMed searched for “AICAR AMPK,” “acadesine,” “AICA riboside,” “ZMP AMPK activation,” and “AICAR exercise mimetic.” Search conducted through April 2026.
Key sources: Merrill et al. (1997) Am J Physiol (PMID: 9435525; foundational characterization); systematic review of AICAR AMPK-independent effects (PMC8147799); GUARDIAN Phase 3 trial (Mack et al. 2002, JAMA); Hardie et al. (multiple review articles on AMPK biology); Winder & Hardie (1996) (exercise AMPK activation context).
Limitations: AICAR/ZMP has well-documented AMPK-independent effects that can confound interpretation of experiments lacking appropriate AMPK-deficient controls. GUARDIAN Phase 3 was negative for the primary endpoint. Not research-grade for any indication. WADA S4 Prohibited. This article is for educational purposes only.
References
- Merrill, G. F., Kurth, E. J., Hardie, D. G., & Winder, W. W. (1997). AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol Endocrinol Metab, 273(6), E1107–E1112. PMID: 9435525
- Winder, W. W., & Hardie, D. G. (1996). Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol, 270(2 Pt 1), E299–304.
- Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012). AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol, 13(4), 251–262.
- Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995). 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem, 229(2), 558–565. (First AICAR as AMPK tool proposal.)
- Mack, M. J., Brown, P. P., Houser, F., Katz, J. D., Katz, M. R., et al. (2002). GUARDIAN trial: acadesine for cardioprotection during cardiac surgery. JAMA. (Phase 3 negative primary endpoint.)
- Herzig, S., & Shaw, R. J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol, 19(2), 121–135. (Comprehensive AMPK biology review.)
- Vincent, M. F., Marangos, P. J., Gruber, H. E., & Van den Berghe, G. (1991). Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes, 40(10), 1259–1266. (AMPK-independent FBPase inhibition.)
- Jansen, R. S., Rosing, H., Schellens, J. H., & Beijnen, J. H. (2011). AICA-riboside formulations. compound Dev Ind Pharm. (AICAR-independent ZMP effects systematic context.)
- Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014). Metformin: from mechanisms of action to therapies. Cell Metab, 20(6), 953–966. (AMPK metabolic disease context; AICAR/metformin parallel mechanisms.)
Frequently Asked Questions
AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; acadesine; CAS: 2627-69-2; MW: ~338.31 Da; YPB.250) is a synthetic nucleoside analog and the most widely used pharmacological AMPK activator in research. AICAR is a procompound: it is phosphorylated intracellularly by adenosine kinase to ZMP, an AMP analog that allosterically activates AMPK by binding the γ subunit AMP-binding sites — mimicking the high-AMP:ATP signal of exercise-induced energy depletion without requiring actual metabolic stress. In research models, AICAR/ZMP-induced AMPK activation drives: (1) ACC phosphorylation/inactivation → malonyl-CoA decrease → CPT1 derepression → fatty acid β-oxidation increase (2.8-fold in Merrill 1997 PMID: 9435525); (2) GLUT4 translocation → insulin-independent glucose uptake; (3) SIRT1 activation → PGC-1α → mitochondrial biogenesis. Important caveat: ZMP also has documented AMPK-independent effects (purine synthesis, FBPase inhibition, cancer cell anti-proliferative effects); AMPK knockout controls are required to attribute effects to AMPK. WADA S4 Prohibited. Research Use Only (RUO). Updated April 2026.
AICAR itself does not activate AMPK directly; it requires intracellular conversion to the active form, ZMP. AICAR (a nucleoside) is taken up by cells via nucleoside transporters and phosphorylated by adenosine kinase to produce ZMP — AICAR monophosphate, also known as 5-aminoimidazole-4-carboxamide ribonucleotide. ZMP is a structural analog of AMP (adenosine monophosphate): it shares the AMP core structure with a modified base (imidazole carboxamide instead of adenine). ZMP binds the γ subunit CBS domain AMP-binding sites of AMPK (the regulatory subunit that senses cellular energy status) and allosterically activates AMPK in the same manner as AMP elevation during exercise. This is why AICAR is described as an “AMP mimic” — but more precisely, ZMP is the AMP mimic, and AICAR is the cell-permeable procompound that generates ZMP inside cells. ZMP is also an endogenous metabolic intermediate in the de novo purine synthesis pathway (between FGAR and SAICAR in the purine ring assembly sequence), which explains its AMPK-independent effects on purine metabolism.
ZMP (the active intracellular form of AICAR) has multiple documented activities beyond AMPK activation that can confound interpretation of experiments. Three major AMPK-independent mechanisms are documented: (1) Fructose-1,6-bisphosphatase (FBPase) inhibition: ZMP directly inhibits the gluconeogenic enzyme FBPase, reducing hepatic glucose output through an AMPK-independent mechanism — some of AICAR’s glucose-lowering effects in diabetic models may reflect this FBPase effect rather than AMPK activation. (2) Purine synthesis pathway effects: as an intermediate in de novo purine synthesis, ZMP accumulation can alter cellular nucleotide pool composition, affecting processes that depend on purine availability (DNA/RNA synthesis, energy metabolism, signal transduction). (3) Direct anti-proliferative effects: AICAR/acadesine induces apoptosis in certain cancer cell lines (B-CLL in particular) through mechanisms that are partially or fully AMPK-independent. The published systematic review (PMC8147799) catalogued these effects comprehensively. To assign effects specifically to AMPK, researchers should include AMPK α2 knockout or dominant-negative AMPK controls. Effects eliminated by AMPK loss-of-function are AMPK-mediated; effects that persist are ZMP-independent. This distinction is essential for mechanistic publications and for comparing AICAR findings to other AMPK activators (like metformin or the direct kinase activator MK-8722) that do not produce ZMP.
AICAR and SLU-PP-332 are the upstream and downstream bookends of the same exercise-adaptation signaling cascade, making them highly complementary research tools rather than redundant alternatives. AICAR activates AMPK via ZMP AMP mimic, mimicking the exercise-induced energy depletion signal at the top of the cascade: AMPK → SIRT1 → PGC-1α → ERRα → mitochondrial biogenesis gene program. SLU-PP-332 activates ERRα directly at the bottom of this cascade, bypassing AMPK and SIRT1 entirely and engaging only the transcriptional endpoint. The research value of running parallel AICAR and SLU-PP-332 experiments is cascade dissection: effects observed with both AICAR and SLU-PP-332 are likely ERRα-transcription-dependent (since that’s the shared endpoint); effects observed with AICAR but not SLU-PP-332 are AMPK-dependent but ERRα-independent; effects observed with SLU-PP-332 but not AICAR (accounting for AICAR’s ZMP-independent effects) would suggest ERRα can be activated by routes other than AMPK/SIRT1/PGC-1α. This kind of mechanistic pharmacological dissection would not be possible with either compound alone.
The GUARDIAN trial evaluated IV acadesine (AICAR) for reduction of composite cardiac events (cardiac death, non-fatal MI, combined stroke) during coronary artery bypass graft surgery. The trial enrolled thousands of research subjects and did not meet its primary composite endpoint in the overall population, though pre-specified subgroup analyses in higher-risk research subjects suggested possible benefit. The trial failure is informative for several reasons. First, AICAR/acadesine’s cardioprotective effects in preclinical models (ischemia-reperfusion protection) did not translate to a clinically significant primary endpoint improvement in the overall surgical population — a common translational challenge where animal model results overestimate human wellness support. Second, IV dosing, timing, and research subjects heterogeneity may have been suboptimal for the specific cardioprotective mechanism. Third, the GUARDIAN data does not invalidate AICAR as a research tool for AMPK biology — it specifically addresses clinical cardioprotection in cardiac surgery and does not speak to AICAR’s established utility as a pharmacological probe for AMPK activation in metabolic, exercise, and diabetes research contexts.
Yes. YourPeptideBrand.com provides white-label dropship for AICAR as YPB.250 (Research Use Only). White-label storefronts include pre-built RUO-compliant product pages with AMPK ZMP-mechanism descriptions, exercise mimetic biology context, AMPK-independent effects caveat, WADA S4 classification notes, and COA library links. Contact the YPB team for confirmed Premier and Core pricing, and use the profit calculator to model projected revenue.
Every AICAR batch includes a lot-specific COA: HPLC purity (≥98%), MS confirmation at ~338.31 Da, optical rotation (AICAR is a ribonucleoside with defined stereochemistry; the β-D configuration is required for adenosine kinase substrate activity and ZMP formation), endotoxin (<1 EU/mg), TAMC, and TYMC. The optical rotation or NMR confirmation of the β-D ribofuranoside configuration is important: the α anomer would not be efficiently phosphorylated by adenosine kinase and would fail to produce ZMP at expected levels. HPLC purity alone does not confirm correct anomer; optical rotation or NMR are the definitive stereochemistry confirmation methods. All lots are traceable through the batch-specific COA library.
The three compounds address exercise adaptation and metabolic biology from three distinct mechanistic entry points, making them highly complementary within a single research catalog. Position AICAR as the upstream AMPK/ZMP exercise signal mimic — the most direct pharmacological activation of the energy-sensing kinase that exercise activates via AMP:ATP ratio change; standard tool for AMPK biology research since 1997 with 3,500+ publications. Position SLU-PP-332 as the downstream ERRα transcription-level exercise mimetic — directly activates the nuclear receptor responsible for encoding exercise adaptation into muscle gene expression; enables ERRα-specific effects to be isolated from the full AMPK cascade. Position MOTS-c as the mitochondria-derived peptide AMPK activator — represents an endogenous mitochondrial signaling pathway linking mitochondrial stress to systemic AMPK activation; distinct from ZMP mechanism. The three compound series makes a compelling catalog narrative: “complete exercise-adaptation signaling toolkit — AMPK (AICAR), ERRα transcription (SLU-PP-332), mitochondrial AMPK peptide (MOTS-c).” Researchers studying any aspect of exercise biology, metabolic disease, or aging will naturally want all three as complementary tools for pathway dissection.
Key Takeaways
Research Takeaways
- Foundational AMPK pharmacological tool (Merrill et al. 1997, PMID: 9435525): Establishes AMPK activation in skeletal muscle via ZMP AMP mimic; 2.8-fold fatty acid oxidation increase; standard AMPK research tool since 1997 with 3,500+ publications.
- Procompound mechanism: AICAR → ZMP (intracellular): Adenosine kinase phosphorylation; ZMP binds AMPK γ subunit AMP-binding sites; allosteric AMPK activation without genuine energy depletion.
- ACC/malonyl-CoA/CPT1 fatty acid oxidation cascade: The primary and most mechanistically specific AICAR/AMPK endpoint in skeletal muscle; CPT1 derepression → fatty acid β-oxidation increase.
- AMPK-independent ZMP effects must be controlled for: FBPase inhibition, purine synthesis, cancer cell anti-proliferative effects are real and documented. AMPK KO/KD controls are required for mechanistic attribution.
- Water-soluble; no DMSO required: Directly dissolved in PBS or culture medium; contrast with SLU-PP-332. Working concentrations in millimolar range (vs. nanomolar for SLU-PP-332).
- Upstream of SLU-PP-332 in the cascade: AMPK → SIRT1 → PGC-1α → ERRα; parallel use with SLU-PP-332 enables cascade dissection.
- GUARDIAN Phase 3 (2002) — primary endpoint not met: IV acadesine for cardiac surgery cardioprotection; does not invalidate AICAR as metabolic/exercise AMPK research tool.
- Optical rotation/NMR for β-D configuration: Required for adenosine kinase substrate activity and ZMP formation; MS cannot confirm stereochemistry.
Business Takeaways
- 3,500+ PubMed publications — one of the most-cited research compounds in the catalog; established research tool audience.
- Only AMPK/ZMP-mechanism activator in YPB catalog — no overlap with SLU-PP-332 (ERRα downstream) or MOTS-c (mitochondrial AMPK).
- AICAR + SLU-PP-332 + MOTS-c exercise trio covers the complete exercise-adaptation signaling cascade from three non-redundant points from a single research buyer audience.
- Contact YPB for confirmed pricing on YPB.250.
Ready to add AICAR to your research catalog? Book a consultation with the YPB team.
[ypb_studies peptide=”aicar”]