Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Affinity for the Histamine H3 Receptor
2.2.2. Acetyl- and Butyrylcholinesterase Inhibition
2.2.3. Human MAO B Inhibition
2.3. Molecular Docking Studies
2.3.1. Molecular Docking to Acetylcholinesterase
2.3.2. Molecular Docking to the Human Butyrylcholinesterase
2.3.3. Molecular Docking to the Human MAO B
2.4. In Vivo Activity of Compound 19
3. Conclusions
4. Materials and Methods
4.1. Chemistry
4.1.1. General Procedure of Synthesis of Compounds 10–15, 18 and 22
4.1.2. 1-(6-[1,1′-Biphenyl]-2-yloxy)hexyl)piperidine Hydrogen Oxalate (10)
4.1.3. 1-(5-([1,1′-Biphenyl]-4-yloxy)pentyl)-3-methylpiperidine Hydrogen Oxalate (11)
4.1.4. 1-(5-([1,1′-Biphenyl]-3-yloxy)pentyl)-3-methylpiperidine Hydrogen Oxalate (12)
4.1.5. 1-(6-([1,1′-Biphenyl]-4-yloxy)hexyl)-3-methylpiperidine Hydrogen Oxalate (13)
4.1.6. 1-(6-([1,1′-Biphenyl]-3-yloxy)hexyl)-3-methylpiperidine Hydrogen Oxalate (14)
4.1.7. 1-(6-([1,1′-Biphenyl]-2-yloxy)hexyl)-3-methylpiperidine Hydrogen Oxalate (15)
4.1.8. 1-(6-([1,1′-Biphenyl]-2-yloxy)hexyl)-4-methylpiperidine Hydrogen Oxalate (18)
4.1.9. 1-(6-([1,1′-Biphenyl]-2-yloxy)hexyl)azepane Hydrogen Oxalate (22)
4.2. In Vitro Biological Studies
4.2.1. Evaluation of Histamine H3 Receptor Affinity
4.2.2. Evaluation of Cholinesterase Inhibitory Activity
4.2.3. Kinetic Studies of eqBuChE Inhibition
4.2.4. Evaluation of Monoamine Oxidase Inhibitory Activity
4.3. Molecular Docking to the Electric Ray Acetylcholinesterase, the Human Butyrylcholinesterase and the Human Monoamine Oxidase B
4.4. In Vivo Studies of Compound 19
4.4.1. Animals
4.4.2. Compound 19 and Reference Compounds
4.4.3. Step-Through Passive Avoidance Task
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Comp. | Cyclic Amine | n | Substitution | hH3R a Ki [nM] Mean ± SD [CI 95%] | eeAChE b IC50 [μM] Mean ± SEM or (% Inh.) e | eqBuChE c IC50 [μM] Mean ± SEM | hMAO B d IC50 [nM] Mean ± SEM or (%Inh.) f |
---|---|---|---|---|---|---|---|
6 | 1 | para | 25.2 ± 9.3 g | (24% ± 1) | 2.16 ± 0.03 | (50% ± 2) | |
7 | 1 | meta | 76.0 ± 9.2 g | (24% ± 1) | 1.29 ± 0.02 | (11% ± 1) | |
8 | 2 | para | 91.5 ± 14.4 g | (48% ± 1) | 1.63 ± 0.05 | (36% ± 13) | |
9 | 2 | meta | 149 ± 108 g | (35% ± 2) | 1.78 ± 0.08 | (16% ± 0) | |
10 | 2 | ortho | 221 [23;2171] | (8% ± 2) | 1.28 ± 0.02 | (40% ± 3) | |
11 | 1 | para | 27.3 ± 15.1 | (45% ± 3) | 0.91 ± 0.01 | (28% ± 3) | |
12 | 1 | meta | 45.0 ± 13.4 | (27% ± 1) | 0.68 ± 0.01 | (5% ± 1) | |
13 | 2 | para | 146.5 ± 65.3 | 5.02 ± 0.09 | 0.95 ± 0.00 | (20% ± 1) | |
14 | 2 | meta | 27 [17;43] | 4.71 ± 0.13 | 1.52 ± 0.04 | (35% ± 6) | |
15 | 2 | ortho | 23 [2;223] | (24% ± 1) | 2.10 ± 0.06 | (16% ± 1) | |
3 | 1 | para | 88.6 ± 31.1 g | (42% ± 1) i | 0.85 ± 0.02 i | (36% ± 2) | |
16 | 1 | meta | 157.0 ± 19.2 g | (41% ± 1) | 1.46 ± 0.03 | (7% ± 1) | |
4 | 2 | para | 265.9 ± 83.7 g | 4.46 ± 0.10 i | 0.74 ± 0.02 i | (27% ± 3) | |
17 | 2 | meta | 172 ± 73 g | (48% ± 1) | 1.49 ± 0.04 | (5% ± 1) | |
18 | 2 | ortho | 561 [192;1638] | (20% ± 3) | 1.48 ± 0.04 | (24% ± 1) | |
19 (E153) | 1 | para | 33.9 ± 8.1 g | (44% ± 1) | 0.59 ± 0.01 | 243 ± 73 (54% ± 1) | |
20 | 1 | meta | 114.7 ± 22.0 g | (26% ± 3) | 0.47 ± 0.01 | (14% ± 0) | |
5 | 2 | para | 150.9 ± 72.8 g | 2.76 ± 0.04 i | 0.60 ± 0.01 i | (45% ± 1) | |
21 | 2 | meta | 19 ± 5.5 g | 3.86 ± 0.08 | 0.87 ± 0.00 | (43% ± 5) | |
22 | 2 | ortho | 528 [328;849] | (30% ± 5) | 0.69 ± 0.05 | (17% ± 0) | |
Pitolisant | 12 ± 3 i | (3% ± 1) i | 8.42 ± 0.18 i | (2% ± 3) | |||
Donepezil | Nt h | 0.041 ± 0.006 i 0.027 ± 0.002 j | 1.83 ± 0.017 i | Nt h | |||
Rivastigmine | Nt h | 71 ± 3 j | 2.20 ± 0.05 | Nt h | |||
Safinamide | Nt h | Nt h | Nt h | 7.7 ± 1.2 |
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Łażewska, D.; Zaręba, P.; Godyń, J.; Doroz-Płonka, A.; Frank, A.; Reiner-Link, D.; Bajda, M.; Stary, D.; Mogilski, S.; Olejarz-Maciej, A.; et al. Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity. Molecules 2021, 26, 3580. https://doi.org/10.3390/molecules26123580
Łażewska D, Zaręba P, Godyń J, Doroz-Płonka A, Frank A, Reiner-Link D, Bajda M, Stary D, Mogilski S, Olejarz-Maciej A, et al. Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity. Molecules. 2021; 26(12):3580. https://doi.org/10.3390/molecules26123580
Chicago/Turabian StyleŁażewska, Dorota, Paula Zaręba, Justyna Godyń, Agata Doroz-Płonka, Annika Frank, David Reiner-Link, Marek Bajda, Dorota Stary, Szczepan Mogilski, Agnieszka Olejarz-Maciej, and et al. 2021. "Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity" Molecules 26, no. 12: 3580. https://doi.org/10.3390/molecules26123580