AICAR (Acadesine / AICA-Riboside)

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What Is AICAR?

AICAR (5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, also known as Acadesine, AICA-Riboside, NSC 105823, or Z-Riboside; CAS 2627-69-2) is a small-molecule purine ribonucleoside analogue and the most-cited pharmacological tool for activating AMP-activated protein kinase (AMPK) in cell-culture, primary-cell, and rodent in-vivo research. It is not a peptide — it is a synthetic ribonucleoside with the molecular formula C₉H₁₄N₄O₅ and a molecular weight of 258.23 g/mol. MedsBase stocks it in the same lyophilized-vial format as our research peptide catalogue for convenience of reconstitution and dosing in mixed-protocol AMPK / metabolic / mitochondrial research.

AICAR was originally developed in the 1990s by Acadesine Inc. (later Schering-Plough) as a candidate cardioprotective agent for coronary artery bypass surgery — the compound completed Phase III trials but did not gain regulatory approval. Its pharmacological utility, however, has only expanded since: AICAR is now the standard reference compound for AMPK activation in published research, and the AMPK pathway it engages has been implicated in nearly every major area of metabolic biology — insulin sensitivity, type-2 diabetes, fatty-acid oxidation, exercise physiology, muscle hypertrophy / atrophy, mitochondrial biogenesis, cancer metabolism, autophagy, and ageing.

In published research AICAR is described as an “exercise mimetic” because chronic administration in sedentary mice has been reported to drive a skeletal-muscle gene-expression signature, mitochondrial-biogenesis programme, and endurance-performance phenotype that broadly mimics the effects of voluntary wheel running — the original 2008 Narkar et al. publication in Cel (“AMPK and PPARδ Agonists Are Exercise Mimetics”) is the most-cited paper in this area. AICAR is also on the WADA Prohibited List (class S4.5, Metabolic Modulators) and is prohibited in sport at all times due to this performance-enhancing potential.

Mechanism of Action — Cellular Activation of AMPK via ZMP

AICAR’s mechanism is the most-characterised of any pharmacological AMPK activator:

• Cell entry via adenosine transporters — AICAR (the riboside) is itself biologically inert. It is taken up into cells through the same equilibrative and concentrative adenosine transporters (ENT1, ENT2, CNT2, CNT3) that move endogenous adenosine and other purine nucleosides across the plasma membrane. Tissue distribution and concentration kinetics in vivo are governed by these transporters.
• Intracellular phosphorylation to ZMP by adenosine kinase — Once intracellular, AICAR is phosphorylated by adenosine kinase (AK) on its 5′-hydroxyl, generating the active metabolite ZMP (5-aminoimidazole-4-carboxamide ribonucleotide). ZMP is the immediate AMP analogue and is the species that actually engages AMPK. Adenosine kinase activity is therefore the rate-limiting step for AICAR pharmacology in any given tissue — research protocols that use AK-deficient cells or AK inhibitors confirm that ZMP, not AICAR itself, is the active species.
• Allosteric activation of AMPK at the γ-subunit — ZMP binds the same Bateman-domain CBS sites on the AMPK γ-subunit that endogenous AMP occupies under low-energy conditions. ZMP binding produces three convergent allosteric effects on AMPK: (1) allosteric stimulation of catalytic activity, (2) protection of Thr172 phosphorylation on the AMPK α-subunit from PP2C dephosphorylation, and (3) enhanced phosphorylation of Thr172 by upstream kinases LKB1 and CaMKK2. The net result is sustained, high-level AMPK activation that is independent of changes in the actual cellular AMP:ATP ratio.
• Downstream metabolic switch — catabolic upregulation — Activated AMPK phosphorylates a large set of metabolic effectors that drive the catabolic / energy-generating programme: ACC (acetyl-CoA carboxylase, on Ser79 and Ser212) — relieving malonyl-CoA inhibition of CPT-I and allowing long-chain fatty acids into the mitochondria for β-oxidation; HSL (hormone-sensitive lipase) — increasing adipocyte lipolysis; TBC1D1 — driving insulin-independent GLUT4 translocation and glucose uptake into skeletal muscle; PGC-1α — driving mitochondrial biogenesis. The skeletal-muscle glucose-uptake effect is the most-cited functional readout in AMPK research.
• Downstream metabolic switch — anabolic suppression — Activated AMPK simultaneously suppresses anabolic / energy-consuming pathways: phosphorylation of TSC2 and Raptor inhibits mTORC1, suppressing protein synthesis and triggering autophagy; phosphorylation of HMG-CoA reductase suppresses cholesterol synthesis; phosphorylation of SREBP1c suppresses hepatic de-novo lipogenesis; phosphorylation of PFKFB3 and ACC suppresses glycogen and fatty-acid synthesis. The combined catabolic-up / anabolic-down switch is the canonical AMPK pharmacology.

The pharmacokinetic profile of AICAR is broadly favourable for research use — oral bioavailability is modest but workable, intraperitoneal administration in rodents produces reliable systemic exposure within 30 minutes, and the plasma half-life of the parent riboside is on the order of 90 minutes (the half-life of the intracellular ZMP metabolite is longer, sustaining AMPK activation for several hours after a single bolus dose). Typical in-vivo rodent protocols use 250–500 mg/kg administered IP daily; high doses (1 g/kg) have been used in some published muscle-physiology research. In-vitro cell culture work typically uses 0.5–2 mM in growth medium.

Published Research Applications

AICAR is used in laboratory research contexts that investigate:

• AMPK pharmacology — the canonical reference activator — by far the most-cited small-molecule AMPK activator in the published literature; standard tool compound for any new AMPK-pathway research; reference compound against which all newer direct AMPK activators (A769662, MK-8722, PF-739, O304, the metformin class) are benchmarked
• Insulin sensitivity and skeletal-muscle glucose uptake — AICAR drives insulin-independent GLUT4 translocation and glucose uptake into skeletal muscle via the AMPK-TBC1D1 axis; widely used in research on type-2 diabetes, insulin-resistance reversal, and skeletal-muscle metabolic flexibility
• Exercise mimetic and endurance research — the Narkar et al. (2008, Cel) “AMPK and PPARδ Agonists Are Exercise Mimetics” framework remains the most-cited paper on AICAR; published rodent protocols document increased endurance, slow-twitch (Type I) fibre conversion, and improved oxidative capacity after 4-week AICAR dosing in sedentary mice
• Hepatic gluconeogenesis and lipogenesis suppression — AICAR suppresses hepatic glucose output via AMPK-mediated phosphorylation of transcriptional co-activators (CRTC2, HNF4α); also suppresses hepatic de-novo lipogenesis via SREBP1c phosphorylation; used in non-alcoholic fatty liver disease (NAFLD) and metabolic-dysfunction-associated steatohepatitis (MASH) preclinical research
• Fatty-acid oxidation research — AICAR phosphorylates ACC, relieves malonyl-CoA inhibition of CPT-I, and drives long-chain fatty acids into the mitochondria for β-oxidation; the canonical pharmacological intervention for upregulating fatty-acid oxidation in primary hepatocytes, cardiomyocytes, and skeletal-muscle myotubes
• Cancer metabolism research — many cancer cells display elevated lipogenesis (via SREBP1c) and elevated mTORC1 signalling; AICAR suppresses both via AMPK activation and has been investigated in published research on acute lymphoblastic leukaemia (the historical original indication for Acadesine), prostate cancer, breast cancer, and other tumour models
• Autophagy and mTORC1-inhibition research — AICAR triggers autophagy via dual phosphorylation of TSC2 (Ser1387) and Raptor (Ser792), both of which inhibit mTORC1; used as a pharmacological intervention in autophagy-induction research alongside rapamycin and starvation models
• Mitochondrial biogenesis research — AICAR drives PGC-1α expression and activity, increasing mitochondrial biogenesis in skeletal muscle and brown adipose tissue; complementary to MOTS-c (mitochondrial-derived AMPK-activating peptide) in protocols that probe AMPK-pathway redundancy
• Cardioprotection research — the original clinical indication; AICAR has been used in ischaemia-reperfusion injury models and the cardiac-surgery cardioprotection paradigm; preclinical research continues despite Phase III not gaining approval

For broader context on AMPK / NAD⁺ / metabolic-axis research compounds in this catalogue, see MOTS-c (mitochondrial-derived peptide AMPK activator — the closest peptide analogue), 5-Amino-1MQ (NNMT-inhibitor; complementary NAD⁺-precursor-sparing approach), NAD⁺ (oxidised dinucleotide coenzyme, central electron-transport substrate), and L-Carnitine (mitochondrial long-chain fatty-acid shuttle). Browse the full research peptides & compounds catalog for related compounds, or see the curated longevity research compounds en fat-loss research peptides hubs.

Beschikbare sterktes en concentraties

MedsBase stocks AICAR in a single lyophilized vial size calibrated to typical in-vivo and high-throughput in-vitro research protocols. The vial is available in 10-vial or 20-vial pack formats:

The 50 mg vial format provides a convenient dosing unit for most published in-vivo rodent protocols and supports the 0.5–2 mM working concentrations used in cell-culture AMPK-activation research. The 20-vial pack is the more economical purchase per-mg for extended-cycle or large-cohort protocols (4–8 week chronic dosing, multi-cohort exercise-mimetic studies). Researchers should determine specific dose ranges from peer-reviewed literature appropriate to the protocol.

How It Compares — AICAR vs MOTS-c

AICAR and MOTS-c are the two most-studied AMPK-activating research compounds in this catalogue, and they target the AMPK pathway via mechanistically distinct routes. AICAR is a small-molecule cell-permeable AMP-mimetic that drives AMPK activation directly at the γ-subunit. MOTS-c is a mitochondrial-derived 16-amino-acid peptide that translocates to the nucleus under metabolic stress and activates AMPK indirectly through a folate-pathway / methionine-cycle intermediate (AICAR-like increase in cellular AICAR / ZMP levels). The two compounds are mechanistically complementary in published combination research, and the comparison illustrates one of the most-studied “small-molecule vs peptide” dyads in AMPK biology.

For research focused on direct, high-magnitude AMPK activation with the canonical small-molecule reference tool, AICAR is the standard compound. For research focused on peptide-class AMPK activation, mitochondrial-derived signalling, or longevity-axis peptide pharmacology, MOTS-c is the more targeted tool. See also 5-Amino-1MQ for NAD-axis precursor-sparing research, SS-31 (Elamipretide) for cardiolipin-binding mitochondrial-targeted research, and NAD⁺ for direct NAD-pool supplementation.

Opslag en Reconstituering

Voor reconstituering: store lyophilized vials refrigerated at 2–8 °C in original packaging for short-term working stock. For long-term storage, freeze unopened vials at −20 °C (stable ≥36 months at −20 °C; ≥12 months at 2–8 °C). Lyophilized AICAR is substantially more stable than most lyophilized peptides because the small-molecule ribonucleoside has no amide bonds or disulfide bridges to hydrolyse. Protect from prolonged exposure to direct light.

Reconstitueringsprocedure: for the 50 mg vial, inject 1.0 mL of bacteriostatic water, sterile water, or sterile PBS down the side wall of the vial — this yields a 50 mg/mL working stock (~193 mM). For more dilute working stocks, 2.5 mL yields 20 mg/mL (~77 mM), and 5.0 mL yields a 10 mg/mL (~39 mM) working stock. AICAR dissolves rapidly with gentle swirling at room temperature; brief warming to 37 °C accelerates dissolution if cold-storage residual crystals are present. For in-vitro cell-culture work, DMSO is also a suitable reconstitution solvent (stock at up to 200 mM); dilute working solutions into aqueous medium just before use, targeting 0.5–2 mM final concentration in growth medium. Once reconstituted in aqueous buffer, store the vial at 2–8 °C and use within 30 days. Protect from light. Discard if cloudiness, particulates, or marked colour change appears.

Veelgestelde vragen

Is AICAR a peptide?

No. AICAR is a small-molecule purine ribonucleoside analogue (MW 258.23 g/mol), niet a peptide. We stock it in our research-peptide catalogue alongside 5-Amino-1MQ, NAD⁺ en L-Carnitine because it serves a complementary role in mitochondrial / metabolic / AMPK-axis research and is supplied in the same lyophilized vial format. The spec table Sequence row is marked “n/a” for this reason.

What is the difference between AICAR, Acadesine, AICA-Riboside, and ZMP?

AICAR, Acadesine, AICA-Riboside, NSC 105823, and Z-Riboside are all the same compound — five different names for 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, the cell-permeable riboside (CAS 2627-69-2). ZMP is a different compound — the intracellular monophosphate (5-aminoimidazole-4-carboxamide ribonucleotide), generated by adenosine kinase from the riboside once it has entered the cell. ZMP is the actual AMP-mimetic that engages AMPK; the riboside itself (AICAR) is the cell-permeable pro-drug. Research suppliers sell the riboside because it is cell-permeable; the monophosphate (ZMP) does not cross the plasma membrane.

Why is AICAR called an “exercise mimetic”?

The Narkar et al. (2008) Cel paper “AMPK and PPARδ Agonists Are Exercise Mimetics” reported that 4 weeks of AICAR administration to sedentary mice (500 mg/kg/d IP) produced a skeletal-muscle gene-expression signature, mitochondrial-biogenesis profile, fibre-type shift toward slow-twitch (Type I) oxidative fibres, and endurance-performance phenotype that broadly mimicked the effects of voluntary wheel running in untreated mice. The “exercise in a pill” framing comes from this paper. AICAR is on the WADA Prohibited List partly because of these performance-enhancing findings.

What published dose ranges have been used in mouse and rat research?

The most-cited mouse-protocol dose is 250–500 mg/kg IP daily, administered for 2–4 weeks. The endurance-phenotype Narkar et al. protocol used 500 mg/kg/d IP for 4 weeks. Higher doses (up to 1 g/kg) have been used in some muscle-physiology research. Rat protocols are similar (250–500 mg/kg IP). In-vitro cell-culture work typically uses 0.5–2 mM AICAR in growth medium. Researchers should consult primary literature (Narkar et al. 2008; Corton et al. 1995 original AMPK-activation paper; Merrill et al. 1997 skeletal-muscle glucose-uptake paper) for species-, model-, and endpoint-specific dosing guidance.

What is the WADA regulatory status of AICAR?

AICAR / Acadesine is listed on the World Anti-Doping Agency (WADA) Prohibited List under class S4.5 (Hormone and Metabolic Modulators) and is prohibited in sport at all times — both in-competition and out-of-competition. The basis is the exercise-mimetic endurance-phenotype finding. Researchers conducting human-subject research with AICAR need to be aware of this status (in addition to regulatory requirements for any unapproved drug). For laboratory in-vitro and rodent in-vivo research the WADA status is informational only.

How does AICAR compare with metformin as an AMPK activator?

Both AICAR and metformin activate AMPK, but through completely different upstream routes. AICAR (after intracellular conversion to ZMP) is a direct AMP-mimetic that binds the AMPK γ-subunit Bateman domain. Metformin is an indirect AMPK activator — it inhibits mitochondrial complex I, which lowers ATP and raises the AMP:ATP ratio, secondarily activating AMPK via the natural AMP-binding mechanism. The two compounds therefore probe different layers of the AMPK pathway: AICAR/ZMP bypasses the requirement for actual energy stress, while metformin engages the natural energy-sensing branch. Newer direct AMPK activators (A769662, MK-8722, PF-739, O304) bind a third site (the ADaM / β-subunit allosteric pocket) and offer better isoform selectivity than either AICAR or metformin.

Can AICAR be combined with MOTS-c, NAD⁺, or 5-Amino-1MQ in research protocols?

Yes — the four compounds target overlapping but mechanistically distinct nodes of mitochondrial / AMPK / NAD-axis biology and are commonly combined in research that aims to dissect direct AMPK activation (AICAR) from peptide-class AMPK activation (MOTS-c), from NAD-precursor-sparing (5-Amino-1MQ), from direct NAD-pool supplementation (NAD⁺). Reconstitute each separately first to establish stability and concentration accuracy, then combine immediately before use rather than co-storing reconstituted vials. The most-published combinations are AICAR + metformin (dual AMPK activation, different upstream branches) and AICAR + rapamycin (dual mTORC1 inhibition, different mechanisms).

Why didn’t Acadesine gain clinical approval?

Acadesine (the clinical-trial name for AICAR) completed two large Phase III trials for cardioprotection in coronary artery bypass surgery (CABG) in the 1990s. The trials did not demonstrate statistically significant reductions in the primary composite endpoint (myocardial infarction, stroke, cardiovascular death), and the development programme was discontinued. AICAR remains a research-tool compound rather than an approved drug, although a number of academic groups have continued to investigate the cardioprotection paradigm and the broader AMPK-pathway pharmacology.

Other Research Compounds for AMPK and Metabolic Research

• MOTS-c — Mitochondrial-derived peptide AMPK activator — closest mechanistic peptide analogue
• 5-Amino-1MQ — Selective NNMT inhibitor — complementary NAD-precursor-sparing approach
• NAD⁺ — Oxidised dinucleotide coenzyme — direct NAD-pool supplementation research
• SS-31 (Elamipretide) — Cardiolipin-binding mitochondrial-targeted peptide
• L-Carnitine — Mitochondrial long-chain fatty-acid shuttle — companion small-molecule
• BAC Water (Bacteriostatisch Water) — Required for reconstituting any lyophilized vial — sterile, 0.9% benzyl-alcohol-preserved diluent

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