Desformylflustrabromine

Desformylflustrabromine (dFBr) is a monomethyltryptamine derivative which was first isolated as a secondary metabolite of the marine bryozoan Flustra foliacea.[1]

Desformylflustrabromine

Clinical data
ATC code	none
Identifiers
IUPAC name 2-[6-bromo-2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl]-N-methylethanamine
CAS Number	474657-72-2
PubChem CID	637026
ChemSpider	552693
Chemical and physical data
Formula	C16H21BrN2
Molar mass	321.262 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C=CC(C)(C)c2[nH]c1cc(Br)ccc1c2CCNC
InChI 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 Key:GQHSCJUTJKLZPX-UHFFFAOYSA-N
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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]

Modulation of nicotonic 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.[7][8] Anti-addictive and pro-cognitive actions have also been demonstrated.[9][10] Furthermore, limited experimental data suggests a potential use in treating the compulsive behaviors seen in OCD.[11]

References

1. Peters L, Wright AD, Kehraus S, Gündisch D, Tilotta MC, König GM (October 2004). "Prenylated indole alkaloids from Flustra foliacea with subtype specific binding on NAChRs". Planta Medica. 70 (10): 883–6. doi:10.1055/s-2004-832610. PMID 15490312.
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): 144–9. 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): 4855–60. doi:10.1016/j.bmcl.2007.06.047. PMC 3633077. PMID 17604168.
4. Lysek N, Rachor E, Lindel T (2002). "Isolation and structure elucidation of deformylflustrabromine from the North Sea bryozoan Flustra foliacea". Zeitschrift für Naturforschung C. 57 (11–12): 1056–61. doi:10.1515/znc-2002-11-1218. PMID 12562094. S2CID 8791934.
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): 42–7. 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): 7259–67. doi:10.1021/jm200834x. PMC 3200116. PMID 21905680.
7. 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. PMID 28809075. S2CID 11131072.
8. 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.
9. 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.
10. Nikiforuk A, Litwa E, Krawczyk M, Popik P, Arias H (March 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.
11. Mitra, Swarup; Mucha, Mckenzie; Khatri, Shailesh N.; Glenon, Richard; Schulte, Marvin K.; Bult-Ito, Abel (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. ISSN 1662-5153. PMC 5214813. PMID 28105008.

Further reading

• 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.