아주대학교

목차

INTRODUCTION 1
MATERIALS AND METHODS 3
1. Materials 3
2. Synthesis and Characterization of CB1R Antagonists 4
3. Tango GPCR β-Arrestin Recruitment Assay 5
4. Animals 6
5. Hypothermia Assay 6
6. Catalepsy Assay 6
7. Radioligand Binding Assay 7
8. cAMP Assay 7
9. β-Arrestin Recruitment Assay 8
10. Pharmacokinetic Study 9
11. Plasma Stability Assay 10
12. Liver Microsomal Stability Assay 10
13. CYP450 Inhibition Assay 11
14. Brain-to-Plasma Distribution Study 12
15. In Vivo Toxicity Study 12
16. IMQ-Induced Psoriasis-Like Mouse Model 13
17. Macrophage Depletion 14
18. Histology and Immunohistochemistry 15
19. Flow Cytometric Analysis 16
20. Cell Culture 16
21. Cell Viability Assay 17
22. Real-Time Quantitative PCR 18
23. Statistical Analysis 18
RESULTS 20
1. Rational design of CB1R antagonists with reduced BBB permeability 20
2. Selection of lead CB1R antagonists with reduced central activity 23
3. In vitro characterization of CB1R binding affinity and functional antagonism 25
4. Pharmacokinetic properties of ACT-B-032 28
5. Plasma and metabolic stability of ACT-B-032 31
6. Reduced brain distribution of ACT-B-032 relative to rimonabant 34
7. CYP inhibition profile of ACT-B-032 36
8. Systemic safety profile of ACT-B-032 38
9. Therapeutic effects of ACT-B-032 in IMQ-induced psoriasis-like skin inflammation 42
10. Comparison of ACT-B-032 and anti-IL-17A antibody treatment in IMQ-induced psoriasis-like skin inflammation 45
11. Modulation of skin barrier-associated markers by ACT-B-032 48
12. Macrophage-dependent therapeutic effects of ACT-B-032 50
13. Suppression of macrophage inflammatory activation by ACT-B-032 54
DISCUSSION 56
REFERENCES 59
ABSTRACT IN KOREAN (국문 초록) 61