Bicuculline

Bicuculline
Clinical data
ATC code	none;
Identifiers
	IUPAC name (6R)-6-[(5S)-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl]furo[3,4-e][1,3]benzodioxol-8(6H)-one;
CAS Number	485-49-4 ;
PubChem CID	10237;
IUPHAR/BPS	2312;
ChemSpider	9820 ;
UNII	Y37615DVKC;
ChEBI	CHEBI:3092 ;
ChEMBL	ChEMBL417990 ;
PDB ligand	H0Z (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID3042687 ;
ECHA InfoCard	100.006.927
Chemical and physical data
Formula	C20H17NO6
Molar mass	367.357 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	215 °C (419 °F)
	SMILES O=C1O[C@H](c3c1c2OCOc2cc3)[C@@H]5c4cc6OCOc6cc4CCN5C;
	InChI InChI=1S/C20H17NO6/c1-21-5-4-10-6-14-15(25-8-24-14)7-12(10)17(21)18-11-2-3-13-19(26-9-23-13)16(11)20(22)27-18/h2-3,6-7,17-18H,4-5,8-9H2,1H3/t17-,18+/m0/s1 ; Key:IYGYMKDQCDOMRE-ZWKOTPCHSA-N ;
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Bicuculline is a phthalide-isoquinoline compound that is a light-sensitive competitive antagonist of GABA_A receptors.^[1] It was originally identified in 1932 in plant alkaloid extracts^[2] and has been isolated from Dicentra cucullaria, Adlumia fungosa, and several Corydalis species (all in subfamily Fumarioideae, previously known as family Fumariaceae). Since it blocks the inhibitory action of GABA receptors, the action of bicuculline mimics epilepsy; it also causes convulsions. This property is utilized in laboratories around the world in the in vitro study of epilepsy, generally in hippocampal or cortical neurons in prepared brain slices from rodents. This compound is also routinely used to isolate glutamatergic (excitatory amino acid) receptor function.

The action of bicuculline is primarily on the ionotropic GABA_A receptors, which are ligand-gated ion channels concerned chiefly with the passing of chloride ions across the cell membrane, thus promoting an inhibitory influence on the target neuron. These receptors are the major targets for benzodiazepines, z-drugs, and related anxiolytic drugs.

The half-maximal inhibitory concentration (IC₅₀) of bicuculline on GABA_A receptors is 2 μM +/-0.1 at 40 μM of GABA (GABA half maximal effective concentration, (EC₅₀)).^[3]

In addition to being a potent GABA_A receptor antagonist, bicuculline can be used to block Ca²⁺-activated potassium channels.^[4]

Sensitivity to bicuculline is defined by IUPHAR as a major criterion in the definition of GABA_A receptors.

References

^ Johnston, Graham AR (2013). "Advantages of an antagonist: bicuculline and other GABA antagonists". British Journal of Pharmacology. 169 (2): 328–336. doi:10.1111/bph.12127. ISSN 1476-5381. PMC 3651659. PMID 23425285.
^ Manske RH (1932). "The Alkaloids of Fumaraceous Plants. II. Dicentra cucullaria (L.) Bernh". Canadian Journal of Research. 7 (3): 265–269. Bibcode:1932CJRes...7..265M. doi:10.1139/cjr32-078.
^ Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston G (2003). "Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2γ2L GABAA receptors". European Journal of Pharmacology. 464 (1): 1–8. doi:10.1016/S0014-2999(03)01344-X. PMID 12600688.
^ Khawaled R, Bruening-Wright A, Adelman JP, Maylie J (August 1999). "Bicuculline block of small-conductance calcium-activated potassium channels". Pflügers Archiv. 438 (3): 314–321. doi:10.1007/s004240050915. PMID 10398861. S2CID 7033568.

[1] Johnston, Graham AR (2013). "Advantages of an antagonist: bicuculline and other GABA antagonists". British Journal of Pharmacology. 169 (2): 328–336. doi:10.1111/bph.12127. ISSN 1476-5381. PMC 3651659. PMID 23425285.

[2] Manske RH (1932). "The Alkaloids of Fumaraceous Plants. II. Dicentra cucullaria (L.) Bernh". Canadian Journal of Research. 7 (3): 265–269. Bibcode:1932CJRes...7..265M. doi:10.1139/cjr32-078.

[3] Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston G (2003). "Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2γ2L GABAA receptors". European Journal of Pharmacology. 464 (1): 1–8. doi:10.1016/S0014-2999(03)01344-X. PMID 12600688.

[4] Khawaled R, Bruening-Wright A, Adelman JP, Maylie J (August 1999). "Bicuculline block of small-conductance calcium-activated potassium channels". Pflügers Archiv. 438 (3): 314–321. doi:10.1007/s004240050915. PMID 10398861. S2CID 7033568.

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Opium components
Alkaloids	16-Hydroxythebaine Berberine Canadine Codamine Coptisine Coreximine Cycloartenone Cyclolaudenol Dehydroreticuline Dihydrosanguinarine Glaucine Isoboldine Isocorypalmine Laudanidine Magnoflorine Narceine Narceinone Norlaudanosoline Norsanguinarine Oripavine Oxysanguinarine Palaudine Papaverrubine B (O-methyl-porphyroxine) Papaverrubine C (epiporphyroxine) Reticuline Salutaridine (sinoacutine) Sanguinarine Scoulerine Somniferine Stepholidine
Morphine group (Phenanthrenes. Includes opioids)	Codeine Morphine Narcotoline Neopine Perparin Papaverrubine D (porphyroxine) Pseudocodeine Pseudomorphine Thebaine
Isoquinolines	Cotarnine Eupaverine Hydrocotarnine Laudanosine Laudanine Noscapine (narcotine) Papaverine Papaveraldine Xanthaline
Protopine group	α-Allocryptopine Corycavamine Corycavine Cryptopine Protopine
Tetrahydroprotoberberine group	Corydaline Corybulbine Isocorybulbine Capaurine
Aporphine group	Dicentrine Glaucine Corytuberine Cularine Corydine Isocorydine Bulbocapnine
Phtalide-isoquinolines	Adulmine Bicuculline Bicucine Corlumine
α-Naphthaphenanthridines	Chelidonine β-Homochelidonoine Chelerythrine Sanguinarine
Other components	Meconic acid Cycloartenol

Neurotoxins
Animal toxins	Batrachotoxin Bestoxin Birtoxin Bungarotoxin Charybdotoxin Conotoxin Fasciculin Huwentoxin Poneratoxin Saxitoxin Tetrodotoxin Vanillotoxin Spooky toxin (SsTx) Epibatidine Zetekitoxin AB Dendrotoxin
Bacterial	Botulinum toxin Tetanospasmin
Cyanotoxins	Anatoxin-a Guanitoxin BMAA Saxitoxin
Plant toxins	Aconitine Bicuculline Penitrem A Picrotoxin Strychnine Tutin Rotenone Ginkgotoxin Cicutoxin Oenanthotoxin Thujone Volkensin Veratridine
Mycotoxins	Ibotenic acid Muscarine Muscimol
Pesticides	Fenpropathrin Tetramethylenedisulfotetramine Bromethalin Crimidine Methamidophos Endosulfan Fipronil Phenylsilatrane Chlorophenylsilatrane Sulfuryl fluoride Mipafox Schradan Dimefox
Nerve agents	Cyclosarin EA-3148 Novichok agent Sarin Soman Tabun VE VG VM VP VR VX GV EA-3990 EA-4056 T-1123 Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide) Fluorotabun Chinese VX EA-2192
Bicyclic phosphates	TBPS TBPO IPTBO
Cholinergic neurotoxins	Acetylcholine mustard Catecholine Choline mustard Ethylcholine mustard Hemicholinium mustard
Psychoactive drugs	Alcohol Nitrous oxide
Other	Dimethylcadmium Dimethylmercury Toxopyrimidine IDPN Tetraethyllead

Convulsants
GABA receptor antagonists	Bicuculline Bicyclic phosphates (TBPS, TBPO, IPTBO) BIDN Bupleurotoxin Chlorophenylsilatrane Cicutoxin Cloflubicyne Coriamyrtin Dihydropicrotoxinin DMCM EBOB Endosulfan FG-7142 Fipronil Flurothyl Gabazine Oenanthotoxin Pentylenetetrazol Phenylsilatrane Picrotoxin p-CN-TBOB p-NCS-TBOB RDX TBOB Tetramethylenedisulfotetramine Thujone Trimethylolpropane phosphite Tutin
GABA synthesis inhibitors	3-Mercaptopropionic acid 4-Deoxypyridoxine Allylglycine Crimidine Decaborane Ginkgotoxin Isoniazid Pentaborane Thiocarbohydrazide Toxopyrimidine
Glycine receptor antagonists	Coriamyrtin Dendrobine Picrotoxin Strychnine Tutin
Glutamate receptor agonists	AMPA Domoic acid Kainic acid NMDA Quisqualic acid Tetrazolylglycine
Convulsant barbiturates	CHEB Diberal (DMBB) McN-481
Other	2,2,3,3-Tetrafluoropropyl trifluoromethyl ether Bromocamphor Camphor FAZ-4 Fluoroethyl fluoroacetate MC-2973 Methionine sulfoximine Methyl fluoroacetate Nitrocyclohexane Thebaine

See also

References