Desformylflustrabromine

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Desformylflustrabromine
Desformylflustrabromine.svg
Clinical data
ATC code
  • none
Identifiers
  • 2-[6-bromo-2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl]-N-methylethanamine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H21BrN2
Molar mass 321.262 g·mol−1
3D model (JSmol)
  • C=CC(C)(C)c2[nH]c1cc(Br)ccc1c2CCNC
  • InChI=1S/C16H21BrN2/c1-5-16(2,3)15-13(8-9-18-4)12-7-6-11(17)10-14(12)19-15/h5-7,10,18-19H,1,8-9H2,2-4H3 X mark.svgN
  • Key:GQHSCJUTJKLZPX-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Desformylflustrabromine (dFBr) is a NMT derivative indole alkaloid which was first isolated from the marine bryozoan Flustra foliacea . [1]

Contents

Bioactivity

dFBr has been identified as a novel positive allosteric modulator of neuronal nicotinic acetylcholine receptor with sub-type specificity for heteromeric receptor with no effect on homomeric sub-type. [2] A recent study has been published which describes the synthesis of water-soluble salts of dFBr and its action has been confirmed as selective potentiator of α4β2 nicotinic acetylcholine receptor responses by using two-electrode voltage clamp whole cell recordings. [3] In the year 2002 it was reported that dFBr was cytotoxic on human colon cancer cell line HCT 116. [4]

Desformylflustrabromine has also been found to be a positive allosteric modulator for the α2β2 subtype of neuronal nicotinic acetylcholine receptor. Additionally it relieves the inhibition of both α2β2 and α4β2 nicotinic acetylcholine receptors by β-Amyloid (1–42) Peptide. [5] Thus desformylflustrabromine can potentially be used in the treatment of Alzheimer's disease. Many of the analogues and derivatives of dFBr are reported to have a potentiating effect on the α4β2 receptors. [6] [7]

Modulation of nicotinic acetylcholine receptor function by desformylflustrabromine has also been found to produce analgesic and anti-allodynic effects in animal models, which could potentially make it of interest for the treatment of neuropathic pain. [8] [9] Anti-addictive and pro-cognitive actions have also been demonstrated. [10] [11] Furthermore, limited experimental data suggests a potential use in treating the compulsive behaviors seen in OCD. [12]

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References

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  2. Sala F, Mulet J, Reddy KP, Bernal JA, Wikman P, Valor LM, et al. (January 2005). "Potentiation of human alpha4beta2 neuronal nicotinic receptors by a Flustra foliacea metabolite". Neuroscience Letters. 373 (2): 144–149. doi:10.1016/j.neulet.2004.10.002. PMID   15567570. S2CID   54375870.
  3. Kim JS, Padnya A, Weltzin M, Edmonds BW, Schulte MK, Glennon RA (September 2007). "Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator". Bioorganic & Medicinal Chemistry Letters. 17 (17): 4855–4860. doi:10.1016/j.bmcl.2007.06.047. PMC   3633077 . PMID   17604168.
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  5. Pandya A, Yakel JL (September 2011). "Allosteric modulator Desformylflustrabromine relieves the inhibition of α2β2 and α4β2 nicotinic acetylcholine receptors by β-amyloid(1-42) peptide". Journal of Molecular Neuroscience. 45 (1): 42–47. doi:10.1007/s12031-011-9509-3. PMC   3235685 . PMID   21424792.
  6. German N, Kim JS, Jain A, Dukat M, Pandya A, Ma Y, et al. (October 2011). "Deconstruction of the α4β2 nicotinic acetylcholine receptor positive allosteric modulator desformylflustrabromine". Journal of Medicinal Chemistry. 54 (20): 7259–7267. doi:10.1021/jm200834x. PMC   3200116 . PMID   21905680.
  7. Dukat M, Jain A, German N, Ferrara-Pontoriero R, Huang Y, Ma Y, et al. (December 2018). "des-Formylflustrabromine (dFBr): A Structure-Activity Study on Its Ability To Potentiate the Action of Acetylcholine at α4β2 Nicotinic Acetylcholine Receptors". ACS Chemical Neuroscience. 9 (12): 2984–2996. doi:10.1021/acschemneuro.8b00156. PMID   30028943. S2CID   51704428.
  8. Bagdas D, Ergun D, Jackson A, Toma W, Schulte MK, Damaj MI (January 2018). "Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain". European Journal of Pain. 22 (1): 84–93. doi:10.1002/ejp.1092. PMC   9829446 . PMID   28809075. S2CID   11131072.
  9. Weggel LA, Pandya AA (March 2019). "Acute Administration of Desformylflustrabromine Relieves Chemically Induced Pain in CD-1 Mice". Molecules. 24 (5): 944. doi: 10.3390/molecules24050944 . PMC   6432607 . PMID   30866543.
  10. Hamouda AK, Jackson A, Bagdas D, Imad Damaj M (June 2018). "Reversal of Nicotine Withdrawal Signs Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Male Mice". Nicotine & Tobacco Research. 20 (7): 903–907. doi:10.1093/ntr/ntx183. PMC   5991208 . PMID   29059422.
  11. Nikiforuk A, Litwa E, Krawczyk M, Popik P, Arias H (June 2020). "Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats". Pharmacological Reports. 72 (3): 589–599. doi: 10.1007/s43440-020-00092-4 . PMC   7329799 . PMID   32207091.
  12. Mitra S, Mucha M, Khatri SN, Glenon R, Schulte MK, Bult-Ito A (2016). "Attenuation of Compulsive-Like Behavior Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Non-Induced Compulsive-Like Mice". Frontiers in Behavioral Neuroscience. 10: 244. doi: 10.3389/fnbeh.2016.00244 . PMC   5214813 . PMID   28105008.

Further reading