Bicuculline methiodide

By employing a Na+-free assay solution and thoroughly disrupting and washing muscle and brain membrane preparations of the American cockroach, reproducible and specific pH] muscimol binding data were obtained (Table IX). This specific muscimol binding was completely inhibited by bicuculline methiodide (10"3 M). 

In order to make this point clear, we attempted to detect specific binding of [3h]DHP, [ H]muscimol and [3H]diazepam to EDTA-treated membranes under the same conditions as that for [3H]Pr-BP binding. Binding should decrease on addition of excess unlabeled ligands if a specific site existed. The binding of [3h]muscimol was reduced on addition of excess muscimol and GABA. Bicuculline methiodide was less potent in displacing [3H]muscimol (Table IV). 

GABA, yaminobutyric acid BPE, bicyclic phosphorus ester DHP, a-dihydropicrotoxinin TBPS, 4-t-butyl-2,6,7-trioxa-l-phosphabicyclo-[2.2.2]octane 1-sulfide Pr-BP, 4-n-propyl-2,6,7-trioxa-l-phospha-bicyclo[2.2.2]octane 1-oxide BP, bicyclic phosphate pb, piperonyl butoxide EDTA, ethylenediaminetetraacetic acid disodium salt BH, bicuculline methiodide... 

Turski, L., Diedrichs, S., Klockgether, T., et al., 1991. Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum. Synapse 7,14-20. 

Bicuculline, C2oHi,06N. (Items 1, 9, 10, 13, 14, 18, 20, 23-26, 34, 35, 38 list, p. 169). This alkaloid exists in two forms, m.p. 177° and m.p. 196°, and has [a], ° + 130- 5° (CHCI3). The hydrochloride has m.p. 259° (dec.) and from the methiodide, W-methylbicuculline, plates, m.p. 246°, has been prepared. Bicuculline contains no methoxyl groups it behaves as a lactone and is convertible by alkalis into bicucine, which is possibly the corresponding hydroxy-aeid (see below). It simulates hydrastine in its reactions and differs from that base by CH, indicating that a methylene-dioxy group replaces two methoxyl groups, and this view is supported by comparison of the products of oxidative hydrolysis of the two alkaloids. Both yield hydrastinine (p. 163) as the basic product, but while hydrastine provides as the second product, opianic acid,... 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Ene lactams can be obtained directly from quaternary phthalideisoquino-linium salts by treating them with concentrated ammonium hydroxide. In this way fumaramine (111) was synthesized from bicuculline (88) methiodide (121,124), fumaridine (113) from methiodides of both diastereomeric / - (91) and a-hydrastines (92) (5,124-126), and narceine imide (116) from narcotine (94) methiodide (122,127,128). In the case of the hydrastines (91 and 92) the Hofmann degradation of their methiodides in ammonia was not stereospecific but yielded the thermodynamically more stable Z isomer (113) (5). It seems, however, that from narcotine (94) a mixture of the Z and E forms was produced rather than a single isomer (123,127). 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

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