Covalent Inhibition of the Histamine H3 Receptor
Abstract
:1. Introduction
2. Results
2.1. Design
2.2. Synthesis
2.3. Structure-Activity Relationship
2.4. Covalent Binding to Glutathione and Nonapeptide
2.5. Covalent Labeling of the H3R by 44
2.6. Functional Characterization
3. Discussion
4. Materials and Methods
4.1. Pharmacology
4.1.1. Materials
4.1.2. Cell Culture and Transfection
4.1.3. Preparation of Cell Homogenates
4.1.4. Radioligand Displacement Assays
4.1.5. Receptor Recovery Assay
4.1.6. [35S]GTPγs Assay
4.1.7. Chemical Stability and Reactivity of 44
4.1.8. Nonapeptide Assay
4.1.9. Data Analysis
4.2. Modelling
4.3. Chemistry
4.3.1. General Information
4.3.2. Synthesis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
[3H]NAMH | [3H]N-α-methylhistamine |
ANOVA | analysis of variance |
DCM | Dichloromethane |
DIPEA | N,N-Diisopropylethylamine |
DME | 1,2-Dimethoxyethane |
DMSO | dimethyl sulfoxide |
GPCR | G protein-coupled receptor |
GSH | glutathion |
GTPγS | guanosine 5′-O-[gamma-thio]triphosphate |
LSD | least significant difference |
MeCN | Acetonitrile |
MIDA | N-methyliminodiacetic acid |
Mp | Melting point |
NP | nonapeptide (KGDYHFPIC) |
SAR | structure-activity relationship |
satd. aq. | saturated aqueous |
SD | standard deviation |
SEM | standard error of mean |
rt | room temperature |
TCI | targeted covalent inhibitors |
TEA | Triethylamine |
Tris | 2-Amino-2-(hydroxymethyl)propane-1,3-diol |
μW | microwave reaction |
wt | wild type |
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Sample Availability: Samples of the compound 44 are available from the authors. |
Cmpd. | Central Ring | R1 | R2 | R3 | pKi | % Unlabeled Receptors |
---|---|---|---|---|---|---|
2 | Pyrimidine | A | Me | phenyl | 7.1 ± 0.1 | 84 ± 16 |
1 | Pyrimidine | A | CH=CH2 | phenyl | < 5 | 41 ± 6 (SD) |
10 | Pyrimidine | B | NH2 | iPr | 7.3 ± 0.1 | 100 ± 0.0 |
34 | Pyrimidine | B | Me | iPr | < 5 | 87 ± 13 |
35 | Pyrimidine | B | Et | iPr | < 5 | 93 ± 7 |
21 | Pyrimidine | B | CH=CH2 | iPr | < 5 | 85 ± 15 |
11 | Pyrimidine | C | NH2 | iPr | 6.7 ± 0.1 | 96 ± 4 |
36 | Pyrimidine | C | Me | iPr | 5.9 ± 0.1 | 96 ± 3 |
37 | Pyrimidine | C | Et | iPr | 5.5 ± 0.1 | 89 ± 11 |
22 | Pyrimidine | C | CH=CH2 | iPr | 5.5 ± 0.0 | 41 ± 9 |
12 | Pyrimidine | C | NH2 | Me | 6.5 ± 0.1 | 91 ± 5 |
23 | Pyrimidine | C | CH=CH2 | Me | 5.4 ± 0.1 | 40 ± 8 |
20 | Pyrimidine | C | C≡CH | Me | < 5 | 80 ± 2 |
42 | Phenyl | C | NH2 | - | 5.9 ± 0.3 | 72 ± 8 |
43 | Phenyl | C | NH-CO-CH2-Cl | - | 6.2 ± 0.1 | 86 ± 5 |
44 | Phenyl | C | N=C=S | - | 6.5 ± 0.3 | 15 ± 2 |
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Share and Cite
Wágner, G.; Mocking, T.A.M.; Kooistra, A.J.; Slynko, I.; Ábrányi-Balogh, P.; Keserű, G.M.; Wijtmans, M.; Vischer, H.F.; de Esch, I.J.P.; Leurs, R. Covalent Inhibition of the Histamine H3 Receptor. Molecules 2019, 24, 4541. https://doi.org/10.3390/molecules24244541
Wágner G, Mocking TAM, Kooistra AJ, Slynko I, Ábrányi-Balogh P, Keserű GM, Wijtmans M, Vischer HF, de Esch IJP, Leurs R. Covalent Inhibition of the Histamine H3 Receptor. Molecules. 2019; 24(24):4541. https://doi.org/10.3390/molecules24244541
Chicago/Turabian StyleWágner, Gábor, Tamara A. M. Mocking, Albert J. Kooistra, Inna Slynko, Péter Ábrányi-Balogh, György M. Keserű, Maikel Wijtmans, Henry F. Vischer, Iwan J. P. de Esch, and Rob Leurs. 2019. "Covalent Inhibition of the Histamine H3 Receptor" Molecules 24, no. 24: 4541. https://doi.org/10.3390/molecules24244541