Imidazoleacetic acid

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Imidazoleacetic acid
Clinical data
Other namesIAA; Imidazole-acetic acid; Imidazole-4-acetic acid; IMA
Routes of
administration		Oral[1]
Drug classGABAA receptor partial agonist; GABAA-ρ receptor antagonist or weak partial agonist; Imidazoline I1 receptor ligand
ATC code
  • None
Identifiers
  • 2-(1H-imidazol-5-yl)acetic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC5H6N2O2
Molar mass126.115 g·mol−1
3D model (JSmol)
  • C1=C(NC=N1)CC(=O)O
  • InChI=1S/C5H6N2O2/c8-5(9)1-4-2-6-3-7-4/h2-3H,1H2,(H,6,7)(H,8,9)
  • Key:PRJKNHOMHKJCEJ-UHFFFAOYSA-N

Imidazoleacetic acid (IAA) or IMA), also known as imidazole-4-acetic acid, is a naturally occurring endogenous metabolite of the neurotransmitter histamine (imidazole-4-ethylamine).[2][3][4][5] It might have a role as an endogenous signaling molecule or neurotransmitter.[6] IAA is formed from histamine by the enzyme diamine oxidase (DAO).[3][2][4]

Pharmacology

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The compound is biologically active, acting as a relatively potent GABAA receptor partial agonist and GABAA-ρ receptor antagonist or weak partial agonist.[2][6] It shows varying activational efficacies or functional selectivity at GABAA receptors of different α subunit compositions, with EmaxTooltip maximal efficacy values ranging from 24 to 72%.[6][7] Unlike certain other GABAA receptor agonists like muscimol, it is not a significant GABA reuptake inhibitor.[5] In addition to its GABA receptor interactions, IAA is an imidazoline I1 receptor ligand.[2] It has relatively low affinity for this receptor however and it is unknown whether it is an agonist or an antagonist.[2] As a metabolite of histamine, it is structurally distinct from other GABAA receptor agonists.[6] Unlike γ-aminobutyric acid (GABA), IAA is orally active and is readily able to cross the blood–brain barrier.[2][6][5]

IAA produces a hypnotic state resembling sleep when administered parenterally to animals.[2] This is often or usually accompanied by seizures.[2] Other effects include hyperactivity, ataxia, catalepsy, analgesia, hypothermia, and hypotension.[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]

Clinical studies

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IAA has been clinically studied in humans, for instance in people with Huntington's disease.[5][2][1] The drug was administered orally and intravenously, 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 rapidly eliminated in humans, which may limit the effects of exogenous IAA.[5][1]

See also

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References

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  1. ^ a b c d e Shoulson I, Chase TN, Roberts E, Van Balgooy JN (September 1975). "Letter: Huntington's disease: treatment with imidazole-4-acetic acid". The New England Journal of Medicine. 293 (10): 504–505. doi:10.1056/NEJM197509042931016. PMID 125382.
  2. ^ a b c d e f g h i j k l m Tunnicliff G (October 1998). "Pharmacology and function of imidazole 4-acetic acid in brain". General Pharmacology. 31 (4): 503–509. doi:10.1016/s0306-3623(98)00079-2. PMID 9792207.
  3. ^ a b Haas HL, Sergeeva OA, Selbach O (July 2008). "Histamine in the nervous system". Physiological Reviews. 88 (3): 1183–1241. doi:10.1152/physrev.00043.2007. PMID 18626069. 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).
  4. ^ a b Tiligada E, Kyriakidis K, Chazot PL, Passani MB (December 2011). "Histamine pharmacology and new CNS drug targets". CNS Neuroscience & Therapeutics. 17 (6): 620–628. doi:10.1111/j.1755-5949.2010.00212.x. PMC 6493842. PMID 22070192. 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].
  5. ^ a b c d e f Krogsgaard-Larsen P, Falch E, Hjeds H (1985). "Heterocyclic analogues of GABA: chemistry, molecular pharmacology and therapeutic aspects". Progress in Medicinal Chemistry. 22: 67–120. doi:10.1016/s0079-6468(08)70229-7. ISBN 978-0-444-80668-0. PMID 3014606.
  6. ^ a b c d e Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry. 2 (8): 817–832. doi:10.2174/1568026023393525. PMID 12171573. 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.
  7. ^ Ebert B, Mortensen M, Thompson SA, Kehler J, Wafford KA, Krogsgaard-Larsen P (June 2001). "Bioisosteric determinants for subtype selectivity of ligands for heteromeric GABA(A) receptors". Bioorganic & Medicinal Chemistry Letters. 11 (12): 1573–1577. doi:10.1016/s0960-894x(01)00184-6. PMID 11412984.