Jiang, Wen Jing
(2024)
Synthesis, Identification, and Biological Evaluation of Orthosteric and Allosteric Ligands Targeting Cannabinoid CB2 Receptors.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The cannabinoid subtype 2 (CB2) receptor presents promising therapeutic potential for various diseases, including osteoporosis, kidney fibrosis, atherosclerosis, and neurodegenerative disorders, while circumventing the psychotropic side effects associated with the CB1 receptor. However, clinical translation has been hindered by limited successful trials and adverse effects linked to CB2-targeted ligands. To overcome these challenges, we proposed an in-silico approach merging transcriptional expression data and computer-aided drug design techniques to expedite drug discovery, minimize costs, and mitigate failure risks with enhanced safety profiles, as these compounds have undergone thorough development or FDA approval. This integrated strategy employs gene-expression signature and 3D molecular fingerprint structure similarity (GES3SS) virtual screening to uncover new therapeutic avenues by exploiting similarities between existing drugs and known CB2 compounds. Moreover, the development of allosteric modulators offers a promising route to enhance specificity and reduce adverse effects. Utilizing the first synthetic CB2 positive allosteric modulator, the EC21a compound, as a reference, the 2-thiohydantoin structure emerges as a proposed scaffold for CB2 allosteric modulators due to its similar pharmacophore to the EC21a compound. Bio-validation of synthesized compounds through competitive binding and cAMP assays provides essential insights into their pharmacological properties and potential efficacy. These approaches expedite the identification of promising CB2-targeted therapies and open new avenues for effective treatment development.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
23 July 2024 |
| Date Type: |
Publication |
| Defense Date: |
27 March 2024 |
| Approval Date: |
23 July 2024 |
| Submission Date: |
19 April 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
187 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
CB2, Allosteric, Ligands, Gene-expression, Drug Repurposing, |
| Date Deposited: |
23 Jul 2024 16:35 |
| Last Modified: |
23 Jul 2024 16:35 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46195 |
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