Aicar vs AOD-9604

Aicar

AICAR, also called acadesine, is 5-aminoimidazole-4-carboxamide riboside: a synthetic nucleoside, not a peptide or an amino-acid derivative. Its monophosphate, ZMP, is a natural intermediate in the pathway cells use to build purine nucleotides. AICAR became a standard laboratory tool because cells convert it to ZMP, which mimics AMP and switches on AMP-activated protein kinase (AMPK). A large body of cell and rodent work has used it to study energy sensing, glucose uptake and fatty-acid metabolism. Human clinical work has been limited and has not centred on metabolism. A known weakness of the tool is that ZMP acts on other AMP-sensitive enzymes too, so not every effect attributed to AICAR runs through AMPK.

AOD-9604

AOD-9604 is a synthetic peptide based on the C-terminal segment of human growth hormone, with a tyrosine at its N-terminus and a disulfide bond. It was designed to test the idea that this short region carries some of growth hormone's activity on fat metabolism separately from the rest of the molecule. Work on it began with rodent studies of fat cells and whole-animal lipid metabolism, and the peptide later entered human clinical trials, whose published record is sparse. A smaller body of animal work has looked at cartilage in joint injury models. Unlike full-length growth hormone, it is not regarded as a growth hormone receptor agonist, which shapes how its reported activity is interpreted.

How Aicar acts

AICAR enters cells through adenosine transporters and is phosphorylated by adenosine kinase to ZMP. ZMP binds the regulatory gamma subunit of AMPK at sites that normally sense AMP, and this allosteric activation, together with increased phosphorylation of the catalytic alpha subunit, raises the kinase's activity. Activated AMPK phosphorylates targets such as acetyl-CoA carboxylase, shifting cells away from lipid synthesis and toward processes that generate ATP. ZMP accumulates to high concentrations, however, and has been reported to affect other AMP-regulated enzymes, including fructose-1,6-bisphosphatase and glycogen phosphorylase. Studies that need to separate AMPK-dependent effects often pair AICAR with genetic knockout models.

How AOD-9604 acts

AOD-9604 has been reported not to bind the growth hormone receptor with meaningful affinity and not to act through the IGF-1 axis, so its proposed actions differ from those of the whole hormone. Studies in isolated rodent fat cells and in obese mice examined lipolysis and lipogenesis, and some of that work implicated beta-3 adrenergic receptor pathways. A receptor that binds the fragment directly has not been identified. The cartilage studies used animal joint injury models and measured markers of cartilage matrix, and no mechanism for those observations has been established. Overall, the mechanistic literature is small and comes from a limited number of groups.

The records side by side

• Type: Aicar, Nucleoside analogue; AOD-9604, Modified hGH fragment (176-191)
• Length: Aicar, not recorded; AOD-9604, 16 amino acids
• Molecular weight: Aicar, 258.23 g/mol; AOD-9604, 1815.1 g/mol
• Molecular formula: Aicar, C9H14N4O5; AOD-9604, C78H123N23O23S2

Reading a comparison

A comparison places two records side by side; it does not merge them. Each description above is drawn from that compound's own record, and the two were not necessarily characterised by the same methods, at the same time, or to the same level of detail. Before comparing any attribute, it is worth establishing that both records describe the substance you think they describe — names are not identifiers, and two entries sharing a name can differ in salt form, stereochemistry or the convention used to state a mass. Where a figure carries no method beside it, the comparison is between two reported numbers rather than between two measurements.