Alda-1

Alda-1
Identifiers
	IUPAC name N-(1,3-Benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide;
CAS Number	349438-38-6;
PubChem CID	831629;
ChemSpider	726276;
ChEBI	CHEBI:94988;
ChEMBL	ChEMBL465952;
CompTox Dashboard (EPA)	DTXSID801324445 ;
Chemical and physical data
Formula	C15H11Cl2NO3
Molar mass	324.16 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Clc1cccc(Cl)c1C(=O)NCc2cc3OCOc3cc2;
	InChI InChI=1S/C15H11Cl2NO3/c16-10-2-1-3-11(17)14(10)15(19)18-7-9-4-5-12-13(6-9)21-8-20-12/h1-6H,7-8H2,(H,18,19); Key:NMKJFZCBCIUYHI-UHFFFAOYSA-N;

Alda-1 is an organic compound that enhances the enzymatic activity of human ALDH2.^[1] Alda-1 has been proposed as a potential treatment for the alcohol flush reaction experienced by people with genetically deficient ALDH2.^[2]

Mechanism of action

Ethanol is metabolized to acetaldehyde in people, which is then metabolized to acetic acid primarily by ALDH2.^[1] People have various ALDH2 alleles. ALDH2*1 is a common allele (wild type), but about 40% of people of East Asian ethnicity have one or two copies of the dominant ALDH2*2 instead, which causes ALDH2 deficiency. If deficient people drink ethanol, they suffer from alcohol flush reaction due to acetaldehyde accumulation.^[3]

Four Alda-1 molecules bind to each monomer of ALDH2 tetramer. This enhances NAD⁺ binding to ALDH2. NAD⁺ is required by ALDH2 for its enzymatic activity,^[4] which is why Alda-1 increases ALDH2 activity by 2.1 fold if ALDH2 is coded by ALDH2*1 and by 11 fold if it is coded ALDH2*2.^[2]

History

Chen et al. first reported Alda-1 in 2008.^[2]^[1] Alda-1 is the first known aldehyde dehydrogenase activator.^[3]

References

^ ^a ^b ^c Ma X, Luo Q, Zhu H, Liu X, Dong Z, Zhang K, et al. (May 2018). "Aldehyde dehydrogenase 2 activation ameliorates CCl₄ -induced chronic liver fibrosis in mice by up-regulating Nrf2/HO-1 antioxidant pathway". Journal of Cellular and Molecular Medicine. 22 (8): 3965–3978. doi:10.1111/jcmm.13677. PMC 6050510. PMID 29799157.
^ ^a ^b ^c Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (September 2008). "Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart". Science. 321 (5895): 1493–5. Bibcode:2008Sci...321.1493C. doi:10.1126/science.1158554. PMC 2741612. PMID 18787169.
^ ^a ^b Mittal M, Bhagwati S, Siddiqi MI, Chattopadhyay N (November 2020). "A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss". European Journal of Pharmacology. 886: 173541. doi:10.1016/j.ejphar.2020.173541. PMID 32896553. S2CID 221540241.
^ Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (January 2014). "Targeting aldehyde dehydrogenase 2: new therapeutic opportunities". Physiological Reviews. 94 (1): 1–34. doi:10.1152/physrev.00017.2013. PMC 3929114. PMID 24382882.

[a-1] Ma X, Luo Q, Zhu H, Liu X, Dong Z, Zhang K, et al. (May 2018). "Aldehyde dehydrogenase 2 activation ameliorates CCl₄ -induced chronic liver fibrosis in mice by up-regulating Nrf2/HO-1 antioxidant pathway". Journal of Cellular and Molecular Medicine. 22 (8): 3965–3978. doi:10.1111/jcmm.13677. PMC 6050510. PMID 29799157.

[b-2] Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (September 2008). "Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart". Science. 321 (5895): 1493–5. Bibcode:2008Sci...321.1493C. doi:10.1126/science.1158554. PMC 2741612. PMID 18787169.

[c-3] Mittal M, Bhagwati S, Siddiqi MI, Chattopadhyay N (November 2020). "A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss". European Journal of Pharmacology. 886: 173541. doi:10.1016/j.ejphar.2020.173541. PMID 32896553. S2CID 221540241.

[4] Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (January 2014). "Targeting aldehyde dehydrogenase 2: new therapeutic opportunities". Physiological Reviews. 94 (1): 1–34. doi:10.1152/physrev.00017.2013. PMC 3929114. PMID 24382882.

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