bilobalide

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 445249903

| IUPAC_name = (5aR-(3aS*,5aα,8b,8aS*,9a,10aα))-9-(1,1-dimethylethyl)-10,10a-dihydro-8,9-dihydroxy-4H,5aH,9H-furo[2,3-b]furo[3',2':2,3]cyclopenta[1,2-c]furan-2,4,7(3H,8H)-trione

| image = bilobalide.svg

| width = 200

| image2 = bilobalide_3d_structure.png

| tradename =

| legal_status = legal

| routes_of_administration = By mouth

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 33570-04-6

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = M81D2O8H7U

| PubChem = 73581

| IUPHAR_ligand = 2366

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 21106418

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 133266

| ChEBI = 3103

| C=15 | H=18 | O=8

| smiles = CC(C)(C)[C@@]1(C[C@H]2[C@@]3([C@]14[C@H](C(=O)O[C@H]4OC3=O)O)CC(=O)O2)O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C15H18O8/c1-12(2,3)14(20)4-6-13(5-7(16)21-6)10(19)23-11-15(13,14)8(17)9(18)22-11/h6,8,11,17,20H,4-5H2,1-3H3/t6-,8-,11-,13-,14+,15?/m0/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = MOLPUWBMSBJXER-ISSLQHLCSA-N

}}

Bilobalide is a biologically active terpenic trilactone present in Ginkgo biloba.{{cite journal | vauthors = van Beek TA, Montoro P | title = Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals | journal = Journal of Chromatography A | volume = 1216 | issue = 11 | pages = 2002–2032 | date = March 2009 | pmid = 19195661 | doi = 10.1016/j.chroma.2009.01.013 }}

Chemistry

Bilobalide is a main constituent of the terpenoids found in Ginkgo leaves. It also exists in minor amounts in the roots. It is a sesquiterpenoid, i.e. it has a 15-carbon skeleton. Its exact synthesis pathway from farnesyl pyrophosphate is still unknown.

Biosynthesis

Bilobalide and ginkgolide have similar biosynthetic pathways. Bilobalide is formed by partially degraded ginkgolide. Bilobalide is derived from geranylgeranyl pyrophosphate (GGPP), which is formed by addition of farnesyl pyrophosphate (FPP) to an isopentenyl pyrophosphate (IPP) unit to form a C₁₅ sesquiterpene. Such formation went through the mevalonate pathway (MVA) and methylerythritol phosphate MEP pathway. In order to generate bilobalide, C₂₀ ginkgolide 13 must form first. To transform from GGPP to abietenyl cation 5, a single bifunctional enzyme abietadiene synthase E1 is required. However, due to the complexity of ginkgolide structures for rearrangement, ring cleavage, and formation of lactone rings, diterpene 8 is used to explain instead. Levopimaradiene 6 and abietatriene 7 are precursors for ginkgolide and bilobalide formation. The unusual tert-butyl substituent is formed from A ring cleavage in 9. Bilobalide 13 then formed in loss of carbons through degradation from ginkgolide 12, and lactones are formed from residual carboxyl and alcohol functions. The end product of bilobalide contains sesquiterpenes and three lactones units.{{cite book | vauthors = Dewick PM | title = Medicinal Natural Products: Products: A Biosynthetic Approach. | edition = Third | publisher = Wiley&Sons | location = West Sussex, England | date = 2009 | pages = 230–232 | isbn = 978-0-470-74168-9 }}

Image:Bilobalide biosynthesis mechanism.JPG

Pharmacology

Bilobalide is important for producing several of the effects of Ginkgo biloba extracts, and it has neuroprotective effects,{{cite journal | vauthors = Defeudis FV | title = Bilobalide and neuroprotection | journal = Pharmacological Research | volume = 46 | issue = 6 | pages = 565–568 | date = December 2002 | pmid = 12457632 | doi = 10.1016/S1043-6618(02)00233-5 }}{{cite journal | vauthors = Kiewert C, Kumar V, Hildmann O, Hartmann J, Hillert M, Klein J | title = Role of glycine receptors and glycine release for the neuroprotective activity of bilobalide | journal = Brain Research | volume = 1201 | pages = 143–150 | date = March 2008 | pmid = 18325484 | doi = 10.1016/j.brainres.2008.01.052 | s2cid = 5191088 }} as well as inducing the liver enzymes CYP3A1 and CYP1A2,{{cite journal | vauthors = Deng Y, Bi HC, Zhao LZ, He F, Liu YQ, Yu JJ, Ou ZM, Ding L, Chen X, Huang ZY, Huang M, Zhou SF | title = Induction of cytochrome P450s by terpene trilactones and flavonoids of the Ginkgo biloba extract EGb 761 in rats | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 38 | issue = 5 | pages = 465–481 | date = May 2008 | pmid = 18421621 | doi = 10.1080/00498250701883233 | s2cid = 84019088 }} which may be partially responsible for interactions between ginkgo and other herbal medicines or pharmaceutical drugs. Bilobalide has recently been found to be a negative allosteric modulator at the GABA_A and GABA_A-rho receptors.{{cite book | vauthors = Johnston GA, Hanrahan JR, Chebib M, Duke RK, Mewett KN | title = GABA | chapter = Modulation of ionotropic GABA receptors by natural products of plant origin | series = Advances in Pharmacology | volume = 54 | pages = 285–316 | date = 2006 | pmid = 17175819 | doi = 10.1016/s1054-3589(06)54012-8 | publisher = Elsevier | isbn = 978-0-12-032957-1 | chapter-url = https://www.sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/376.pdf | access-date = 2024-05-04 | archive-url = https://web.archive.org/web/20201109012745/https://www.sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/376.pdf | archive-date = 9 November 2020 | url-status = dead }} Of GABA_A, it may possibly be selective for the subunits predominantly implicated in cognitive and memory functioning such as α1{{Citation needed|date=December 2014}}.