Discovery of hit compounds targeting the peripheral tissue cannabinoid type 1 receptor for psoriasis treatment
- 주제(키워드) Cannabinoid 1 receptor , antagonist , psoriasis , inflammatory skin diseases , peripheral tissue specific function , BBB permeability
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 Eunha Kim
- 발행년도 2025
- 학위수여년월 2025. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000034456
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Psoriasis is a chronic autoimmune inflammatory disease primarily affecting the skin. It is also associated with an increased risk of complications, such as cardiovascular diseases (CVDs) and psoriatic arthritis (PsA), due to the cumulative effects of systemic inflammation. Current therapeutic approaches focus on symptom alleviation and disease progression control rather than providing a fundamental cure. Recognizing psoriasis as a chronic inflammatory systemic disease (CIDs), we propose a novel and fundamental therapeutic strategy by targeting the cannabinoid 1 receptor (CB1R), a key regulator of systemic immune modulation. In this study, we aimed to overcome the limitations of existing CB1R antagonists, including low receptor affinity and adverse central nervous system (CNS) effects caused by blood- brain barrier (BBB) penetration. To address these challenges, we designed and synthesized a series of derivatives incorporating various aliphatic, alicyclic, or aromatic functional groups. By assessing their receptor affinity and BBB permeability, we performed a structure-activity relationship (SAR) study to identify substituents exhibiting favorable trends. Through this process, we identified hit compounds of peripheral tissue-specific CB1R antagonist. These results provide insight into the design of new derivatives with improved pharmacological properties.
more목차
1. Introduction 1
2. Result and discussion 6
2.1. Synthetic plan Design of AJ5012 & AJ5018 derivatives 6
2.2. SAR of AJ5012 derivatives : Binding affinity about CB1R & CB2R 9
2.3. SAR of AJ5018 derivatives : Binding affinity about CB1R & CB2R 15
2.4. Confirmation of BBB permeability with LC/MS 21
3. Conclusion 30
4 Experimental 31
4.1. General information 31
4.2. Synthesis of AJ5012 derivatives 32
4.3. Synthesis of AJ5018 derivatives 44
4.4. Tango GPCR Assay 63
4.5. Mice 63
4.6. Preparation of ex vivo samples for BBB permeability assay with LC/MS 64
4.7. Measurement conditions of LC/MS for BBB permeability assay 64
REFERENCES 65
APPENDIX 74
1. Supporting information 74
2. 1H and 13C NMR spectra of compounds 80
3. LC chromatogram of compounds 131
ABSTRACT IN KOREAN (국문초록) 139
