Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts
| Autor: | Günther H.J. Peters, Jesper T. Andreasen, François Crestey, Jesper L. Kristensen, Christian Soerensen, Anders A. Jensen, Charlotte Busk Magnus |
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| Rok vydání: | 2018 |
| Předmět: |
Agonist
alpha7 Nicotinic Acetylcholine Receptor medicine.drug_class Stereochemistry Nicotinic Antagonists Receptors Nicotinic 010402 general chemistry 01 natural sciences Mice Tetrahydroisoquinolines Drug Discovery medicine Animals Humans Nicotinic Antagonist Receptor Swimming Acetylcholine receptor 010405 organic chemistry Chemistry Antagonist Stereoisomerism Antidepressive Agents 0104 chemical sciences Molecular Docking Simulation Nicotinic acetylcholine receptor Nicotinic agonist Docking (molecular) Molecular Medicine Salts |
| Zdroj: | Crestey, F, Jensen, A A, Soerensen, C, Magnus, C B, Andreasen, J T, 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, vol. 61, no. 4, pp. 1719-1729 . https://doi.org/10.1021/acs.jmedchem.7b01895 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01895 |
| Popis: | 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 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 slightly more potent α4β2 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. |
| Databáze: | OpenAIRE |
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