4-AHP

Pharmaceutical compound From Wikipedia, the free encyclopedia

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

Other names4-(Aminomethyl)-1-hydroxypyrazole

Drug classGABA_A receptor agonist

ATC code

None

PubChem CID

71582755

Quick facts Clinical data, Other names ...

4-AHP
Clinical data

Other names	4-(Aminomethyl)-1-hydroxypyrazole
Drug class	GABA_A receptor agonist
ATC code	None
Identifiers
IUPAC name (1-hydroxypyrazol-4-yl)methanamine
PubChem CID	71582755
ChemSpider	29396889
ChEMBL	ChEMBL2315213
Chemical and physical data
Formula	C₄H₇N₃O
Molar mass	113.120 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1=C(C=NN1O)CN
InChI InChI=1S/C4H7N3O/c5-1-4-2-6-7(8)3-4/h2-3,8H,1,5H2 Key:SGFQVPARKZCZOT-UHFFFAOYSA-N

Pharmacology

The drug is a moderately potent and high-efficacy partial to full agonist of the GABA_A receptor (R_maxTooltip maximal efficacy = 69–108%).^[1]^[3]^[4] It is less potent as a GABA_A 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 GABA_A-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 GABA_A 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 GABA_A receptor binding and activation.^[6] A number of derivatives of 4-AHP have been synthesized and studied as GABA_A receptor ligands.^[1]^[4]^[7]

References

[1]
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]
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]
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]
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 GABA_A Receptor Agonists (PDF). EFMC International Symposium on Medicinal Chemistry Manchester, UK Aug. 28 - Sept. 1, 2016. pp. P278.

4-AHP

Pharmacology

Development

References

External links

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