4-AHP

Last updated

4-AHP
4-AHP.svg
Clinical data
Other names4-(Aminomethyl)-1-hydroxypyrazole
Drug class GABAA receptor agonist
ATC code
  • None
Identifiers
  • (1-hydroxypyrazol-4-yl)methanamine
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C4H7N3O
Molar mass 113.120 g·mol−1
3D model (JSmol)
  • C1=C(C=NN1O)CN
  • InChI=1S/C4H7N3O/c5-1-4-2-6-7(8)3-4/h2-3,8H,1,5H2
  • Key:SGFQVPARKZCZOT-UHFFFAOYSA-N

4-AHP, also known as 4-(aminomethyl)-1-hydroxypyrazole, is a synthetic GABAA receptor agonist related to the alkaloid and Amanita muscaria constituent muscimol. [1] [2] [3] [4]

Contents

Pharmacology

The drug is a moderately potent and high-efficacy partial to full agonist of the GABAA receptor (Rmax Tooltip maximal efficacy = 69–108%). [1] [3] [4] It is less potent as a GABAA receptor agonist than γ-aminobutyric acid (GABA), muscimol, or gaboxadol (THIP) (e.g., ~30-fold lower affinity and ~24-fold lower activational potency than muscimol), but shows a similar functional activity profile relative to those of GABA and muscimol. [1] [4] The drug is also a high-efficacy partial agonist of the GABAA-ρ receptor (~4-fold less potent than muscimol). [4] It does not appear to have been evaluated in animals and its effects are unknown. [1] [2] [4] 4-AHP is a close analogue of muscimol, in which the isoxazole ring has been replaced with a pyrazole ring. [1] [2] [3] [4]

Development

4-AHP was first described in the scientific literature by 2013. [1] [4] It is one of only a few known analogues of muscimol that have been found to act as high-efficacy GABAA receptor agonists, along with other related compounds such as dihydromuscimol, thiomuscimol, and gaboxadol. [1] [3] [2] [5] This can be attributed to the very strict structural requirements for GABAA receptor binding and activation. [6] A number of derivatives of 4-AHP have been synthesized and studied as GABAA receptor ligands. [1] [4] [7]

References

  1. 1 2 3 4 5 6 7 8 Petersen JG, Bergmann R, Krogsgaard-Larsen P, Balle T, Frølund B (June 2014). "Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres". Neurochemical Research. 39 (6): 1005–1015. doi:10.1007/s11064-013-1226-6. PMID   24362592.
  2. 1 2 3 4 Rivera-Illanes D, Recabarren-Gajardo G (September 2024). "Classics in Chemical Neuroscience: Muscimol". ACS Chemical Neuroscience. 15 (18): 3257–3269. doi:10.1021/acschemneuro.4c00304. PMID   39254100. Other derivatives of muscimol were explored, including thiomuscimol (40), substituting the isoxazole ring for an isothiazole ring. 4- PIOL (41), a piperidine substituted isoxazole which led to low efficacy and partial agonism, the dihydroisoxazole derivative dihydromuscimol (42) and pyrazole ring analogs, such as azamuscimol (43) and 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) (44) were also developed (Table 4).78−81
  3. 1 2 3 4 Kowalczyk P, Kulig K (2014). "GABA system as a target for new drugs". Current Medicinal Chemistry. 21 (28): 3294–3309. doi:10.2174/0929867321666140601202158. PMID   24934345. Another series of GABAA-receptor antagonists were developed as analogues of muscimol. The performed studies identified the 1-hydroxypyrazole scaffold as a bioisosteric replacement for 3-isoxazolol in muscimol within the GABAA receptors. The unsubstituted 4-AHP (6) ([3H]muscimol binding Ki (μM) 0.22; α1b2γ2S IEC50 (μM) 13; ρ1 EC50 (μM) 3.1) was found to be a moderately potent agonist (Fig. 5). The SAR studies showed that substitutions in 3- and 5- positions were detrimental to binding affinities [21].
  4. 1 2 3 4 5 6 7 8 Petersen JG, Bergmann R, Møller HA, Jørgensen CG, Nielsen B, Kehler J, et al. (February 2013). "Synthesis and biological evaluation of 4-(aminomethyl)-1-hydroxypyrazole analogues of muscimol as γ-aminobutyric acid(a) receptor agonists". Journal of Medicinal Chemistry. 56 (3): 993–1006. doi:10.1021/jm301473k. PMID   23294161.
  5. ↑ Krogsgaard-Larsen P (2018). "THIP/Gaboxadol, a Unique GABA Agonist". Reference Module in Biomedical Sciences. Elsevier. doi:10.1016/b978-0-12-801238-3.97290-8. ISBN   978-0-12-801238-3 . Retrieved 7 October 2025. Numerous attempts to develop pharmacologically interesting analogs of gaboxadol during the past few decades have failed. This small, bicyclic, and conformationally frozen molecule is unique and constitutes its own structural type of GABA agonist. Gaboxadol is the drug of choice for studies of the physiological role(s) of extrasynaptic GABAA receptors, and the toxicological and pharmacokinetic properties of the compound allows scientists to extend such studies into animal behavioral experiments and ultimately clinical studies.
  6. ↑ Krogsgaard-Larsen P, Frølund B, Liljefors T (2006). "GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic1". GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Adv Pharmacol. Vol. 54. pp. 53–71. doi:10.1016/s1054-3589(06)54003-7. ISBN   978-0-12-032957-1. PMID   17175810.
  7. ↑ Grinberga S, Damgaard M, Andersen V, Jensen AA, Krogsgaard-Larsen P, Nielsen B, et al. (2016). Synthesis and Pharmacological Evaluation of Amidine Containing GABAA Receptor Agonists (PDF). EFMC International Symposium on Medicinal Chemistry Manchester, UK Aug. 28 - Sept. 1, 2016. pp. P278.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.