Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors

Research output: Contribution to journal › Journal article › Research › peer-review

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Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors. / Gasiorek, Agnes; Trattnig, Sarah M.; Ahring, Philip K.; Kristiansen, Uffe; Frølund, Bente; Frederiksen, Kristen; Jensen, Anders A.

In: Biochemical Pharmacology, Vol. 110-111, 2016, p. 92-108.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Gasiorek, A, Trattnig, SM, Ahring, PK, Kristiansen, U, Frølund, B, Frederiksen, K & Jensen, AA 2016, 'Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors', Biochemical Pharmacology, vol. 110-111, pp. 92-108. https://doi.org/10.1016/j.bcp.2016.04.004

APA

Gasiorek, A., Trattnig, S. M., Ahring, P. K., Kristiansen, U., Frølund, B., Frederiksen, K., & Jensen, A. A. (2016). Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors. Biochemical Pharmacology, 110-111, 92-108. https://doi.org/10.1016/j.bcp.2016.04.004

Vancouver

Gasiorek A, Trattnig SM, Ahring PK, Kristiansen U, Frølund B, Frederiksen K et al. Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors. Biochemical Pharmacology. 2016;110-111:92-108. https://doi.org/10.1016/j.bcp.2016.04.004

Author

Gasiorek, Agnes ; Trattnig, Sarah M. ; Ahring, Philip K. ; Kristiansen, Uffe ; Frølund, Bente ; Frederiksen, Kristen ; Jensen, Anders A. / Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors. In: Biochemical Pharmacology. 2016 ; Vol. 110-111. pp. 92-108.

Bibtex

@article{966dd06d999744e7b75961ef2ebaafe2,
title = "Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors",
abstract = "We have previously identified a novel class of 5-hydroxytryptamine type 3 receptor (5-HT3R) agonists sharing little structural similarity with orthosteric 5-HT3R ligands (J{\o}rgensen et al., 2011). In the present study we have elucidated the functional characteristics and the mechanism of action of one of these compounds, trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA). In electrophysiological recordings TMPPAA was found to be a highly-efficacious partial agonist equipotent with 5-HT at the 5-HT3A receptor (5-HT3AR) expressed in COS-7 cells and somewhat less potent at the receptor expressed in Xenopus oocytes. The desensitization kinetics of TMPPAA-evoked currents were very different from those mediated by 5-HT. Moreover, repeated TMPPAA applications resulted in progressive current run-down and persistent non-responsiveness of the receptor to TMPPAA, but not to 5-HT. In addition to its direct activation, TMPPAA potentiated 5-HT-mediated 5-HT3AR signalling, and the allosteric link between the two binding sites was corroborated by the analogous ability of 5-HT to potentiate TMPPAA-evoked responses. The agonism and potentiation exerted by TMPPAA at a chimeric α7-nACh/5-HT3A receptor suggested that the ligand acts through the transmembrane domain of 5-HT3AR, a notion further substantiated by its functional properties at chimeric and mutant human/murine 5-HT3ARs. A residue in the transmembrane helix 4 of 5-HT3A was identified as an important molecular determinant for the different agonist potencies exhibited by TMPPAA at human and murine 5-HT3ARs. In conclusion, TMPPAA is a novel allosteric agonist and positive allosteric modulator of 5-HT3Rs, and its aberrant signalling characteristics compared to 5-HT at the 5-HT3AR underline the potential in Cys-loop receptor modulation and activation through allosteric sites.",
author = "Agnes Gasiorek and Trattnig, {Sarah M.} and Ahring, {Philip K.} and Uffe Kristiansen and Bente Fr{\o}lund and Kristen Frederiksen and Jensen, {Anders A.}",
year = "2016",
doi = "10.1016/j.bcp.2016.04.004",
language = "English",
volume = "110-111",
pages = "92--108",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Delineation of the functional properties and the mechanism of action of TMPPAA, an allosteric agonist and positive allosteric modulator of 5-HT3 Receptors

AU - Gasiorek, Agnes

AU - Trattnig, Sarah M.

AU - Ahring, Philip K.

AU - Kristiansen, Uffe

AU - Frølund, Bente

AU - Frederiksen, Kristen

AU - Jensen, Anders A.

PY - 2016

Y1 - 2016

N2 - We have previously identified a novel class of 5-hydroxytryptamine type 3 receptor (5-HT3R) agonists sharing little structural similarity with orthosteric 5-HT3R ligands (Jørgensen et al., 2011). In the present study we have elucidated the functional characteristics and the mechanism of action of one of these compounds, trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA). In electrophysiological recordings TMPPAA was found to be a highly-efficacious partial agonist equipotent with 5-HT at the 5-HT3A receptor (5-HT3AR) expressed in COS-7 cells and somewhat less potent at the receptor expressed in Xenopus oocytes. The desensitization kinetics of TMPPAA-evoked currents were very different from those mediated by 5-HT. Moreover, repeated TMPPAA applications resulted in progressive current run-down and persistent non-responsiveness of the receptor to TMPPAA, but not to 5-HT. In addition to its direct activation, TMPPAA potentiated 5-HT-mediated 5-HT3AR signalling, and the allosteric link between the two binding sites was corroborated by the analogous ability of 5-HT to potentiate TMPPAA-evoked responses. The agonism and potentiation exerted by TMPPAA at a chimeric α7-nACh/5-HT3A receptor suggested that the ligand acts through the transmembrane domain of 5-HT3AR, a notion further substantiated by its functional properties at chimeric and mutant human/murine 5-HT3ARs. A residue in the transmembrane helix 4 of 5-HT3A was identified as an important molecular determinant for the different agonist potencies exhibited by TMPPAA at human and murine 5-HT3ARs. In conclusion, TMPPAA is a novel allosteric agonist and positive allosteric modulator of 5-HT3Rs, and its aberrant signalling characteristics compared to 5-HT at the 5-HT3AR underline the potential in Cys-loop receptor modulation and activation through allosteric sites.

AB - We have previously identified a novel class of 5-hydroxytryptamine type 3 receptor (5-HT3R) agonists sharing little structural similarity with orthosteric 5-HT3R ligands (Jørgensen et al., 2011). In the present study we have elucidated the functional characteristics and the mechanism of action of one of these compounds, trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA). In electrophysiological recordings TMPPAA was found to be a highly-efficacious partial agonist equipotent with 5-HT at the 5-HT3A receptor (5-HT3AR) expressed in COS-7 cells and somewhat less potent at the receptor expressed in Xenopus oocytes. The desensitization kinetics of TMPPAA-evoked currents were very different from those mediated by 5-HT. Moreover, repeated TMPPAA applications resulted in progressive current run-down and persistent non-responsiveness of the receptor to TMPPAA, but not to 5-HT. In addition to its direct activation, TMPPAA potentiated 5-HT-mediated 5-HT3AR signalling, and the allosteric link between the two binding sites was corroborated by the analogous ability of 5-HT to potentiate TMPPAA-evoked responses. The agonism and potentiation exerted by TMPPAA at a chimeric α7-nACh/5-HT3A receptor suggested that the ligand acts through the transmembrane domain of 5-HT3AR, a notion further substantiated by its functional properties at chimeric and mutant human/murine 5-HT3ARs. A residue in the transmembrane helix 4 of 5-HT3A was identified as an important molecular determinant for the different agonist potencies exhibited by TMPPAA at human and murine 5-HT3ARs. In conclusion, TMPPAA is a novel allosteric agonist and positive allosteric modulator of 5-HT3Rs, and its aberrant signalling characteristics compared to 5-HT at the 5-HT3AR underline the potential in Cys-loop receptor modulation and activation through allosteric sites.

U2 - 10.1016/j.bcp.2016.04.004

DO - 10.1016/j.bcp.2016.04.004

M3 - Journal article

C2 - 27086281

VL - 110-111

SP - 92

EP - 108

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -

ID: 160100337