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

François Crestey; Anders A. Jensen; Christian Soerensen; Charlotte Busk Magnus; Jesper Andreasen T.; Günther Herbert Johannes Peters; Jesper Langgaard Kristensen

doi:10.1021/acs.jmedchem.7b01895

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

François Crestey, Anders A. Jensen, Christian Soerensen, Charlotte Busk Magnus, Jesper Andreasen T., Günther Herbert Johannes Peters, Jesper Langgaard Kristensen

6 Citations (Scopus)

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 potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K _i and functional IC ₅₀ 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 slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβη. 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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	61
Pages (from-to)	1719-1729
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01895
Publication status	Published - 22 Feb 2018

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10.1021/acs.jmedchem.7b01895

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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

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 et al.

In: Journal of Medicinal Chemistry, Vol. 61, 22.02.2018, p. 1719-1729.

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

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

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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 potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K i and functional IC 50 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 slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβη. 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}",

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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 - 2018/2/22

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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 potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K i and functional IC 50 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 slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβη. 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 potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K i and functional IC 50 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 slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβη. 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

SN - 0022-2623

VL - 61

SP - 1719

EP - 1729

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

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

Abstract

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