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| Other names | IAA; Imidazole-acetic acid; Imidazole-4-acetic acid; IMA; I4AA |
| Routes of administration | Oral[1] |
| Drug class | GABAA receptorpartial agonist;GABAA-ρ receptorantagonist or weak partial agonist;ImidazolineI1 receptorligand |
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| Formula | C5H6N2O2 |
| Molar mass | 126.115 g·mol−1 |
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Imidazoleacetic acid (also known asIAA,IMA,imidazole-4-acetic acid, orI4AA) is anaturally occurringendogenousmetabolite of theneurotransmitterhistamine (imidazole-4-ethylamine).[2][3][4][5] It might have a role as an endogenoussignalingmolecule orneurotransmitter.[6] IAA is formed from histamine by theenzymediamine oxidase (DAO).[3][2][4]
The compound isbiologically active, acting as a relativelypotentGABAA receptorpartial agonist andGABAA-ρ receptorantagonist or weak partial agonist.[2][6] It shows varyingactivationalefficacies orfunctional selectivity at GABAA receptors of different αsubunit compositions, withEmaxTooltip maximal efficacy values ranging from 24 to 72%.[6][7] Unlike certain other GABAA receptor agonists likemuscimol, it is not a significantGABA reuptake inhibitor.[5] In addition to itsGABA receptor interactions, IAA is animidazolineI1 receptorligand.[2] It has relatively lowaffinity for this receptor however and it is unknown whether it is anagonist or an antagonist.[2] As a metabolite of histamine, it isstructurally distinct from other GABAA receptor agonists.[6] Unlikeγ-aminobutyric acid (GABA), IAA isorally active and is readily able to cross theblood–brain barrier.[2][6][5]
IAA produces ahypnotic state resemblingsleep when administeredparenterally to animals.[2] This is often or usually accompanied byseizures.[2] Other effects includehyperactivity,ataxia,catalepsy,analgesia,hypothermia, andhypotension.[2] Most of these effects are thought to be due to the compound's GABAA receptor interactions.[2] The hypotensive effects of IAA might be mediated by imidazoline I1 receptor activation, although GABAA receptor activation could alternatively explain these particular effects.[2]
IAA has beenclinically studied in humans, for instance in people withHuntington's disease.[5][2][1] The drug was administeredorally andintravenously, which appeared to successfully elevate circulating IAA concentrations.[1] However, IAA did not produce behavioral or motor changes in the patients nor did it improve condition symptoms even when given at very high doses.[5][2][1] It is possible that IAA may be rapidlyeliminated in humans, which may limit the effects ofexogenous IAA.[5][1]
The main histamine-degrading enzyme in peripheral tissues (gut, connective tissues) and in invertebrates is diamine oxidase (DAO), which directly converts histamine into imidazoleacetic acid. DAO activity in the brain is negligibly low under basal conditions, but when HNMT is inhibited may represent a salvage pathway for production of imidazoleacetic acid, an effective GABAA receptor agonist (266, 596).
Histamine acts postsynaptically via H1, H2, H3, and H4 receptors, and it is inactivated by methylation through neuronal histamine N-methyltransferase (HNMT, EC 2.1.1.8), without excluding the contribution of diamine oxidase (DAO, EC 1.4.3.6), which converts histamine into imidazole acetic acid, a γ -aminobutyric acid (GABA)A receptor agonist [cf. Ref. 3].
The histamine metabolite imidazole4-acetic acid (IAA) represents another structural class of ligands and has been shown to be a relatively potent GABAA agonist and a GABAC antagonist [30]. IAA readily penetrates the blood-brain barrier (BBB) and may play a role as a central and/or peripheral endogenous GABAA receptor ligand. [...] As observed for THIP, the heterocyclic GABA isosteres IAA and P4S show the characteristics of a partial GABAA agonist [61, 63]. [...] As illustrated in Fig. (7), the pattern of GABAA receptor subunit dependence of the maximal response of THIP and IAA are qualitatively the same as that of P4S. [...] Fig. (7). Subunit dependent efficacy of isoguvacine, THIP, P4S and IAA. [...] As described above functional selectivity is obtainable for a number of compounds like the GABA agonists IAA and THIP. IAA and THIP display a highly subunit dependent potency and maximal response resulting in functional selectivity. At some combinations, the compounds may act as agonists and, at the same time, as antagonists or low efficacy partial agonists at other combinations.
