Comparison of clenbuterol enantiomers using four psychopharmacological tests sensitive to β-agonists

Martin, Patrick; Puech, A; Brochet, Denis; Soubrié, Philippe; Simon, Pierre

doi:10.1016/0014-2999(85)90481-9

Cited by 18 publications

(6 citation statements)

References 5 publications

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“…This lack of direct activity at the spinal level, the finding that isoproterenol exerts an analgesic activity after ICV administration (Gardella et al 1970), and the data presented here support the hypothesis that beta-adrenoceptor agonists may have antinociceptive properties due to a central effect on a modulatory system. The effect of clenbuterol was stereospecific, as were other central effects of this drug in mice (Martin et al 1985). Interestingly, the effects of isoproterenol on the tooth pulp assay and on the acetic acid-induced writhing test were also stereospecific, the (-)-isomer being the active form (Gardella et al 1970;Bentley et al 1983).…”

Section: Discussionmentioning

confidence: 85%

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

et al. 1986

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Clenbuterol, isoproterenol and salbutamol increased the latency in the licking response of mice on the hot plate at 56.5 degrees C. This effect was dose-related and obtained after IP administration. Clenbuterol was active at lower doses than isoproterenol and salbutamol, a result which is consistent with its better penetration in the central nervous system. Moreover, the effect of clenbuterol was stereospecific, the (-)-isomer being the active form. Our results suggest the implication of central beta-adrenoceptors in the modulation of the response to a painful stimulation.

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Section: Discussionmentioning

confidence: 85%

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

et al. 1986

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“…First, the lipophilic β 1 -adrenoceptor agonist prenalterol (which like clenbuterol penetrates the blood-brain barrier) was examined in the traditional MES test in a dose of 10 mg/kg s.c. and failed to exhibit anticonvulsant effects (Fischer and Müller 1988). Second, the doses causing anticonvulsant effects in the present study (low mg range) are much higher than those eliciting β 2 -adrenoceptor-mediated behavioural responses in the study of Martin et al (1985;µg range). Third, the degree of stereoselectivity for the anticonvulsant effect of clenbuterol [the (-)-enantiomer being 1.7 times as potent as the (+)-enantiomer] is much lower than the stereoselectivity for β 2 -adrenoceptor-mediated behavioural responses (factor of >17; Martin et al 1985).…”

Section: Concentration-dependent Inhibition Of Peak I Namentioning

confidence: 90%

“…Second, the doses causing anticonvulsant effects in the present study (low mg range) are much higher than those eliciting β 2 -adrenoceptor-mediated behavioural responses in the study of Martin et al (1985;µg range). Third, the degree of stereoselectivity for the anticonvulsant effect of clenbuterol [the (-)-enantiomer being 1.7 times as potent as the (+)-enantiomer] is much lower than the stereoselectivity for β 2 -adrenoceptor-mediated behavioural responses (factor of >17; Martin et al 1985). In contrast to the specific effects of the (-)-enantiomer at β 2 -receptors, the local anaesthetic potency of both enantiomers was not different (Engelhardt, personal communications).…”

Section: Concentration-dependent Inhibition Of Peak I Namentioning

confidence: 90%

Anticonvulsant and sodium channel blocking activity of higher doses of clenbuterol

Fischer

Kittner

Regenthal

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

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Clenbuterol, a lipophilic beta2-adrenoceptor agonist, was investigated in various seizure models of experimental epilepsy. In the maximal electroshock seizure threshold test, clenbuterol (> or =4 mg/kg i.p.) increased the electroconvulsive threshold for tonic seizures in mice. In the traditional maximal electroshock seizure (MES) test in mice, ED50 values of 11 mg/kg i.p. or s.c. were determined. In both models, the beta2-receptor antagonist ICI 118.551 did not antagonize the anticonvulsant activity of clenbuterol. Combinations of clenbuterol with standard antiepileptics revealed additive anticonvulsant effects. Repeated administration of clenbuterol (5 mg/kg s.c., twice daily for 14 days) to mice did not significantly influence its anticonvulsant potency or the effectiveness of phenobarbital in the MES test. In various chemically-induced seizure tests with tonic convulsions, clenbuterol inhibited or tended to suppress the tonic phase. However, this drug was not effective in preventing clonic seizures in the pentylenetetrazol (85 mg/kg s.c.) seizure threshold test. In the rotarod ataxia test (mice), a minimal "neurotoxic" dose (TD50) of 41 mg/kg i.p. was determined. In unrestrained rats with chronically implanted electrodes in the dorsal hippocampus, clenbuterol (2 mg/kg and 4 mg/kg i.p.) significantly reduced the duration of electrically evoked hippocampal afterdischarges. In amygdala-kindled rats, clenbuterol (5 mg/kg and 10 mg/kg i.p.) reduced the seizure severity to stage 3. Additional studies indicated that clenbuterol (6 mg/kg i.p.) increased the heart rate and decreased the blood pressure, but this drug did not alter the plasma level of the two tested antiepileptics phenobarbital and carbamazepine. Furthermore, in whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes, clenbuterol (1-100 microM) depressed the fast sodium current in a concentration- and frequency-dependent manner. In conclusion, the anticonvulsant effects of higher doses of clenbuterol against generalized tonic-clonic and complex partial seizures seem to be related to the inhibition of voltage-dependent sodium channels and not to the modulation of beta-adrenoceptors.

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“…Previously it has been reported that (S)-clenbuterol had neuroprotective properties, caused reduced blood pressure and enhanced blood glucose levels in rats. While (R)-clenbuterol did not promote these properties, it was found that it caused decreased motor activity, head twitches and tremors [8,9]. Upon examination of human urine of participants who ingested racemic clenbuterol, it was found that the S-enantiomer is longer retained in the body [10].…”

Section: Introductionmentioning

confidence: 99%

Chemo-Enzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and other β2- Agonists

Blindheim¹,

Hansen²,

Evjen³

et al. 2018

Preprint

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(R)-1-(4-Amino-3,5-dichlorophenyl)-2-bromoethan-1-ol has been synthesised in 93% enantiomeric excess (ee) by asymmetric reduction of the corresponding ketone catalysed by a ketoreductase and NADPH as the co-factor in DMSO. (S)-N-(2,6-Dichloro-4-(1-hydroxyethyl)phenyl)acetamide has been synthesised in >98% ee by the same system. Both synthons are potential precursors for clenbuterol enantiomers. Clenbuterol is a β2-agonist used in veterinary treatment of asthma in several countries. The drug is listed on the World Anti-doping Agency’s Prohibited list due to its effect on increased protein synthesis in the body. However, racemic clenbuterol has recently been shown to reduce the risk of Parkinson’s disease. In order to reveal which one (or both) of the enantiomers that cause this effect, the pure enantiomers need to be studied separately. Our biocatalytic approach in order to obtain enantiopure clenbuterol should be applicable to industrial scale.

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Comparison of clenbuterol enantiomers using four psychopharmacological tests sensitive to β-agonists

Cited by 18 publications

References 5 publications

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

Anticonvulsant and sodium channel blocking activity of higher doses of clenbuterol

Chemo-Enzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and other β2- Agonists

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Comparison of clenbuterol enantiomers using four psychopharmacological tests sensitive to β-agonists

Cited by 18 publications

References 5 publications

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

Antinociceptive activity of beta-adrenoceptor agonists in the hot plate test in mice

Anticonvulsant and sodium channel blocking activity of higher doses of clenbuterol

Chemo-Enzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and other &beta;2- Agonists

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Chemo-Enzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and other β2- Agonists