Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

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

Standard

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts. / Crestey, François; Jensen, Anders A.; Soerensen, Christian; Magnus, Charlotte Busk; Andreasen T., Jesper; Peters, Günther Herbert Johannes; Kristensen, Jesper Langgaard.

In: Journal of Medicinal Chemistry, Vol. 61, 2018, p. 1719-1729.

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

Harvard

Crestey, F, Jensen, AA, Soerensen, C, Magnus, CB, Andreasen T., J, Peters, GHJ & Kristensen, JL 2018, 'Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts', Journal of Medicinal Chemistry, vol. 61, pp. 1719-1729. https://doi.org/10.1021/acs.jmedchem.7b01895

APA

Crestey, F., Jensen, A. A., Soerensen, C., Magnus, C. B., Andreasen T., J., Peters, G. H. J., & Kristensen, J. L. (2018). Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts. Journal of Medicinal Chemistry, 61, 1719-1729. https://doi.org/10.1021/acs.jmedchem.7b01895

Vancouver

Crestey F, Jensen AA, Soerensen C, Magnus CB, Andreasen T. J, Peters GHJ et al. Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts. Journal of Medicinal Chemistry. 2018;61:1719-1729. https://doi.org/10.1021/acs.jmedchem.7b01895

Author

Crestey, François ; Jensen, Anders A. ; Soerensen, Christian ; Magnus, Charlotte Busk ; Andreasen T., Jesper ; Peters, Günther Herbert Johannes ; Kristensen, Jesper Langgaard. / Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61. pp. 1719-1729.

Bibtex

@article{5ec5ce3abea743c4b94614d83f36fd2d,
title = "Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts",
abstract = "We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more portent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightlymore potent antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication.",
author = "Fran{\c c}ois Crestey and Jensen, {Anders A.} and Christian Soerensen and Magnus, {Charlotte Busk} and {Andreasen T.}, Jesper and Peters, {G{\"u}nther Herbert Johannes} and Kristensen, {Jesper Langgaard}",
year = "2018",
doi = "10.1021/acs.jmedchem.7b01895",
language = "English",
volume = "61",
pages = "1719--1729",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

}

RIS

TY - JOUR

T1 - Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

AU - Crestey, François

AU - Jensen, Anders A.

AU - Soerensen, Christian

AU - Magnus, Charlotte Busk

AU - Andreasen T., Jesper

AU - Peters, Günther Herbert Johannes

AU - Kristensen, Jesper Langgaard

PY - 2018

Y1 - 2018

N2 - We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more portent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightlymore potent antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication.

AB - We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more portent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding Ki and functional IC50 values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightlymore potent antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication.

U2 - 10.1021/acs.jmedchem.7b01895

DO - 10.1021/acs.jmedchem.7b01895

M3 - Journal article

C2 - 29384668

VL - 61

SP - 1719

EP - 1729

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -

ID: 189155613