Abecarnil is a Full Agonist at Some, and a Partial Agonist at Other Recombinant GABAA Receptor Subtypes

Pribilla, I.; Neuhaus, René; Huba, R.; Hillmann, Margrit; Turner, Jonathan D.; Stephens, D.N.; Schneider, Havah

doi:10.1007/978-3-642-78451-4_5

Cited by 25 publications

(16 citation statements)

References 10 publications

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“…In the different a-isoform coexpressed with p, and 72 in mammalian cells, the receptors containing the a,-subunit displayed the properties of BZ, receptors whilst the receptors containing a2-, a3 or a5-subunits dis played the properties of BZ2 receptors (23,24). Thus, our present studies suggest that abecarnil may be a selective ligand for the GABAA receptor containing the a,-subunit, which is consistent with the preliminary evidence on recon stituted GABAA receptors in frog oocytes (25). As to the intrinsic activity, the GABA ratio is likely to represent the average intrinsic activity for a given substance at a variety of GABAA/BZ receptors.…”

Section: Discussionsupporting

confidence: 90%

Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Ozawa¹,

Nakada²,

Sugimachi³

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-~-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5 10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki=0.24 nM) with a higher affinity than to rat spinal cord BZ2 receptors (Ki=1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ, receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecar nil may act as a selective partial agonist at central BZ, receptors, resulting in its potent anticonflict and tam ing effects with little sedative and ataxic effects.

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Section: Discussionsupporting

confidence: 90%

Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Ozawa¹,

Nakada²,

Sugimachi³

et al. 1994

Japanese Journal of Pharmacology

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“…In the case of abecarnil, its efficacy at some receptor subunit composition was reported to be low (Ozawa et al, 1994;Vorobjev et al, 1995). The drug shows some receptor subtype selectivity (Pribilla et al, 1993), which may limit its potency to disinhibit exploratory behavior, in our behavioral model. Furthermore, a 30-fold higher affinity of abecarnil for receptor containing the al subunit than for other receptor isoforms, and its full agonist activity at c~1 subunit containing receptors may explain the similarity of behavioral effects of abecarnil and zolpidem (Pribilla et al, 1993;Knoflach et al, 1993).…”

Section: Discussionmentioning

confidence: 96%

“…The drug shows some receptor subtype selectivity (Pribilla et al, 1993), which may limit its potency to disinhibit exploratory behavior, in our behavioral model. Furthermore, a 30-fold higher affinity of abecarnil for receptor containing the al subunit than for other receptor isoforms, and its full agonist activity at c~1 subunit containing receptors may explain the similarity of behavioral effects of abecarnil and zolpidem (Pribilla et al, 1993;Knoflach et al, 1993). It may therefore be postulated, that the pronounced sedative effect of this drug in the OFT depends on a higher efficacy at subtype 1 of the BDZ-GABAA receptor, which makes its profile of action akin to that of zolpidem.…”

Section: Discussionmentioning

confidence: 99%

Benzodiazepine-GABAA receptor complex ligands in two models of anxiety

Nazar

Jessa

Płaźnik

1997

J. Neural Transmission

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In the present study, the actions of several compounds with different intrinsic activities and BDZ receptor selectivity were examined in two well established animal models of anxiety: the open field test (OFT) and Vogel's punished drinking text (VT). Full agonists at the BDZ GABAA receptor (midazolam and diazepam) showed anxiolytic-like effects in both tests; however, the doses necessary to disinhibit animal behavior controlled by fear were higher in the VT than in the OFT. None of the partial BDZ receptor agonists studied (bretazenil, Ro 19-8022 and abecarnil) diminished neophobia-like behavior of rats in the OFT, and their sedative influence on gross behavior prevailed. On the other hand, all three drugs produced a clear-cut anxiolytic effect in the VT. A selective BDZ, receptor subtype full agonist (zolpidem) had a similar profile of action to that of partial agonists with an even stronger sedative effect in the OFT. Alpidem (a selective BDZ1 receptor partial agonist) did not reveal any anxiolytic action in either test. Flumazenil (an antagonist at the BDZ-GABAA receptors) also produced no effect in the OFT, or the VT. An inverse BDZ receptor agonist, beta-carboline-3-carboxylate methyl ester (beta-CCM), evoked an anxiogenic-like response in the OFT, but not in the VT. In summary, it appeared that partial agonists and selective ligands at BDZ1 receptors revealed less advantageous anxiolytic-like action than did full allosteric GABAA receptor modulators. This study also indicates the test dependent profiles of action of BDZ-GABAA receptor ligands. It also indirectly suggests a different neurobiological background underlying the applied tests.

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“…Abecarnil, a ␤-carboline that acts at BDZ receptors, markedly reduces dependence potential compared with BDZs in rodents, dogs, cats, and in non-human primates (12)(13)(14)(15). Although abecarnil acts as a high-affinity full agonist at BDZ receptors containing ␣ 1 subunits, it may act as a partial agonist at other receptor subtypes (16). Surprisingly, in mice, replacement of alprazolam treatment with abecarnil (for 1 week) reduced the severity of signs of alprazolam withdrawal during the course of treatment with abecarnil, and prevented the emergence of the alprazolam discontinuation syndrome after abrupt termination of the therapy with abecarnil.…”

Section: Discussionmentioning

confidence: 99%

Alprazolam dependence prevented by substituting with the β-carboline abecarnil

Pinna¹,

Galici²,

Schneider³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Abrupt termination of the treatment of humans with benzodiazepines (BDZs) leads to a rapid onset of discontinuation syndrome characterized by anxiety, muscle spasms, and occasionally convulsions. For this reason, it is recommended in clinical practice to reduce the dose of the BDZs gradually at the end of treatment. Nevertheless, many clinicians report signs of dependence even during gradual reduction of doses (tapering) of the BDZs in a large proportion of patients. Thus, there is considerable interest in discovering means of weaning patients away from BDZs without the risk of discontinuation syndrome. In the present study, mice withdrawn from chronic treatment with alprazolam showed anxiety, muscle rigidity, and seizures between days 1 and 28 after termination of the treatment. Replacement of alprazolam with the ␤-carboline abecarnil for 7 days prevented the occurrence of the signs of dependence. In contrast, substitution of the ␤-carboline antagonist ethyl-5-isopropoxy-4-methyl-␤-carboline-3-carboxylate (ZK93426) for alprazolam worsened the discontinuation syndrome. Replacement therapy with abecarnil after long-term treatment with the BDZs offers a novel method for rapid tapering.

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Abecarnil is a Full Agonist at Some, and a Partial Agonist at Other Recombinant GABAA Receptor Subtypes

Cited by 25 publications

References 10 publications

Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Benzodiazepine-GABAA receptor complex ligands in two models of anxiety

Alprazolam dependence prevented by substituting with the β-carboline abecarnil

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