The biological activity of d-baclofen (Lipresal®)

Olpe, H.-R.; Demieville, Henri; Baltzer, V.; Bencze, W. L.; Koella, Werner P.; Wolf, Peter; Haas, Helmut L.

doi:10.1016/0014-2999(78)90032-8

Cited by 212 publications

(81 citation statements)

References 6 publications

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“…This study revealed that the biological activity of racemic baclofen resides with the (-)-enantiomer. Interestingly, the (-)-enantiomer was less active than would have been expected had the dose of racemate been doubled, a phenomenon which has been observed in other systems (Olpe et al, 1978).…”

Section: Discussionmentioning

confidence: 58%

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Andrews

Wood

1986

British J Pharmacology

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Section: Discussionmentioning

confidence: 58%

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Andrews

Wood

1986

British J Pharmacology

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“…It is not known whether GABAB sites are implicated in the central depressant effect but the (-)-isomer is the active form not only in binding studies but also in depressing neuronal activity (Olpe, Demieville, Baltzer, Bencze & Koella, 1978). However, the action of baclofen may not be confined to GABAB receptors.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes

Bowery

Hill

Hudson

1983

British J Pharmacology

391

116

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Saturable binding of (±)‐[3H]‐baclofen and [3H]‐γ‐aminobutyric acid ([3H]‐GABA) to rat brain crude synaptic membranes has been examined by means of a centrifugation assay. The binding of [3H]‐baclofen could be detected in fresh or previously frozen tissue and was dependent on the presence of physiological concentrations of Ca2+ or Mg2+ although a lower affinity Na+‐dependent component could also be observed. Both components probably reflect binding to receptor recognition sites. The saturable portion of bound [3H]‐baclofen formed 20.3 ± 6.9% of total bound ligand. This could be displaced by GABA (IC50 =.0.04 μm), (−)‐baclofen (0.04 μm) and to a much lesser extent by (+)‐baclofen (33 μm). Isoguvacine, piperidine‐4‐sulphonic acid and bicuculline methobromide were inactive (up to 100 μm) and muscimol was only weakly active (IC50 = 12.3 μm). Saturable binding of [3H]‐GABA increased on adding CaCl2 or MgSO4 (up to 2.5 mm and 5.0 mm respectively) to the Tris‐HCl incubation solution. This binding (GABAB site binding) was additional to the bicuculline‐sensitive binding of GABA (GABAA site binding) and could be completely displaced by (−)‐baclofen (IC50 = 0.13 μm). Increasing the Ca2+ concentration (0 to 2.5 mm) increased the binding capacity of the membranes without changing their affinity for the ligand. The binding of [3H]‐GABA to GABAB sites could be demonstrated in fresh as well as previously frozen membranes with a doubling of the affinity being produced by freezing. Further incubation with the non‐ionic detergent Triton‐X‐100 (0.05% v/v) reduced the binding capacity by 50%. The pharmacological profile of displacers of [3H]‐GABA from GABAB sites correlated well with that for [3H]‐baclofen displacement. A correlation with data previously obtained in isolated preparations of rat atria and mouse vas deferens was also apparent. It is concluded that [3H]‐baclofen or [3H]‐GABA are both ligands for the same bicuculline‐insensitive, divalent cation‐dependent binding sites in the rat brain.

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“…(300 MHz) analysis and further confirmed by HPLC analysis of enantiomer is much more active but also more toxic than the (+) the diastereomeric amides, obtained by reaction of mono-ester 5 enantiomer (3)(4)(5). The R configuration was assigned to the more with (R)-1-(phen~l)ethylamine in the presence of 1-(3-dimethactive enantiomer on the basis of X-ray crystallography (6).…”

Section: Baclofen or 4 -A M I N 0 -3 -( 4 -~H L~~o~h~~~l ) B~t~~~i~mentioning

confidence: 77%

Chemoenzymatic enantioselective synthesis of baclofen

Chênevert¹,

Desjardins²

1994

Can. J. Chem.

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ROBERT C&NEVERT and MICHEL DESJARDINS. Can. J. Chem. 72.23 12 (1 994).We report two different chemoenzymatic enantioselective syntheses of baclofen based on the distinction between enantiotopic ester groups in compounds bearing a prochiral centre. In the first approach, the key step is the highly stereoselective enzymatic hydrolysis of dimethyl3-(4-chlorophenyl)glutarate by chymotrypsin in an aqueous medium. In the second approach, the key step is the enzyme-catalyzed esterification of 2-(4-chloropheny1)-1,3-propanediol by acetic anhydride in the presence of a lipase in an organic medium.ROBERT C&NEVERT et MICHEL DESIARDINS. Can. J. Chem. 72,2312 (1994.Nous dCcrivons deux syntheses chimio-enzymatiques des Cnantiomeres du baclofen basCes sur une distinction de groupements ester Cnantiotopiques dans des composCs comportant un centre prochiral. Dans la premiere approche, 1'Ctape-clC est une hydrolyse stCrCosClective du 3-(4-chlorophCnyl)glutarate de dimCthyle par la chymotrypsine en milieu aqueux. Dans la seconde approche, I'Ctape-clC est une estCrification enzymatique du 2-(4-ch1orophCnyl)-l,3-propanediol par I'anhydride acCtique en presence d'une lipase en milieu organique.. . Introduction(PLE) could recognize 4 as substrate. Thus, when compound 4 The neutral amino acid 7-aminobutyric acid (GABA) is an Was hydrolyzed in aqueous buffer (pH 7.7) under the catalysis inhibitory neurotransmitter related to the control of neuronal of chymotrypsin, chiral mono-ester (R)-5 was obtained in 85% activity in the central nervous system and to the regulation of yield and with a high enantiomeric excess (ee r 98%). he several physiological mechanisms (1). GABA has been shown enzymatic reaction was indicated by a decrease of PH, which to act through at least two different receptor sites with different was maintained at its initial value by the addition of aqueous

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The biological activity of d-baclofen (Lipresal®)

Cited by 212 publications

References 6 publications

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes

Chemoenzymatic enantioselective synthesis of baclofen

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The biological activity of d-baclofen (Lipresal®)

Cited by 212 publications

References 6 publications

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat

Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes

Chemoenzymatic enantioselective synthesis of baclofen

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Characteristics of GABA_B receptor binding sites on rat whole brain synaptic membranes