Development of Yin-Yang ligand for cannabinoid receptors
Copyright © 2023 Elsevier Inc. All rights reserved..
Cannabinoid receptors (CBs), including CB1 and CB2, are the key components of a lipid signaling endocannabinoid system (ECS). Development of synthetic cannabinoids has been attractive to modulate ECS functions. CB1 and CB2 are structurally closely related subtypes but with distinct functions. While most efforts focus on the development of selective ligands for single subtype to circumvent the undesired off-target effect, Yin-Yang ligands with opposite pharmacological activities simultaneously on two subtypes, offer unique therapeutic potential. Herein we report the development of a new Yin-Yang ligand which functions as an antagonist for CB1 and concurrently an agonist for CB2. We found that in the pyrazole-cored scaffold, the arm of N1-phenyl group could be a switch, modification of which yielded various ligands with distinct activities. As such, the ortho-morpholine substitution exerted the desired Yin-Yang bifunctionality which, based on the docking study and molecular dynamic simulation, was proposed to be resulted from the hydrogen bonding with S173 and S285 in CB1 and CB2, respectively. Our results demonstrated the feasibility of structure guided ligand evolution for challenging Yin-Yang ligand.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
|---|---|
| Enthalten in: |
Bioorganic chemistry - 133(2023) vom: 15. Apr., Seite 106377 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Qiu, Yanli [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 26.04.2023 Date Revised 26.04.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bioorg.2023.106377 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM352415207 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM352415207 | ||
| 003 | DE-627 | ||
| 005 | 20231226053656.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bioorg.2023.106377 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1174.xml |
| 035 | |a (DE-627)NLM352415207 | ||
| 035 | |a (NLM)36731294 | ||
| 035 | |a (PII)S0045-2068(23)00037-8 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Qiu, Yanli |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Development of Yin-Yang ligand for cannabinoid receptors |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.04.2023 | ||
| 500 | |a Date Revised 26.04.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Cannabinoid receptors (CBs), including CB1 and CB2, are the key components of a lipid signaling endocannabinoid system (ECS). Development of synthetic cannabinoids has been attractive to modulate ECS functions. CB1 and CB2 are structurally closely related subtypes but with distinct functions. While most efforts focus on the development of selective ligands for single subtype to circumvent the undesired off-target effect, Yin-Yang ligands with opposite pharmacological activities simultaneously on two subtypes, offer unique therapeutic potential. Herein we report the development of a new Yin-Yang ligand which functions as an antagonist for CB1 and concurrently an agonist for CB2. We found that in the pyrazole-cored scaffold, the arm of N1-phenyl group could be a switch, modification of which yielded various ligands with distinct activities. As such, the ortho-morpholine substitution exerted the desired Yin-Yang bifunctionality which, based on the docking study and molecular dynamic simulation, was proposed to be resulted from the hydrogen bonding with S173 and S285 in CB1 and CB2, respectively. Our results demonstrated the feasibility of structure guided ligand evolution for challenging Yin-Yang ligand | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cannabinoid receptors | |
| 650 | 4 | |a Docking and simulation | |
| 650 | 4 | |a Drug design | |
| 650 | 4 | |a Subtype selectivity | |
| 650 | 4 | |a Yin-Yang ligand | |
| 650 | 7 | |a Cannabinoids |2 NLM | |
| 650 | 7 | |a Endocannabinoids |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Receptor, Cannabinoid, CB1 |2 NLM | |
| 650 | 7 | |a Receptors, Cannabinoid |2 NLM | |
| 700 | 1 | |a Zhao, Yitian |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Meifang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Cuixia |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Weiliang |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xiaodi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Suwen |e verfasserin |4 aut | |
| 700 | 1 | |a Tao, Houchao |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic chemistry |d 1986 |g 133(2023) vom: 15. Apr., Seite 106377 |w (DE-627)NLM012846570 |x 1090-2120 |7 nnns |
| 773 | 1 | 8 | |g volume:133 |g year:2023 |g day:15 |g month:04 |g pages:106377 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bioorg.2023.106377 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 133 |j 2023 |b 15 |c 04 |h 106377 | ||