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Design, Synthesis, and Biological Validation of Allosteric Modulators for Cannabinoid Two (CB2) Receptor

Yang, Bo (2023) Design, Synthesis, and Biological Validation of Allosteric Modulators for Cannabinoid Two (CB2) Receptor. Master's Thesis, University of Pittsburgh. (Unpublished)

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The cannabinoid receptor subtype 2 (CB2) belongs to the class A GPCR family and is an ideal therapeutic target because of its involvement in multiple diseases. However, it is difficult to selectively target CB2 due to the largely conserved orthosteric binding site across receptor subtypes. Developing allosteric modulators (AMs) could provide subtype selectivity and other therapeutic advantages like celling effect and biased signaling. In chapter 2, we designed and synthesized tri-substituted sulfonamide and urea compounds as potential CB2 negative allosteric modulators (NAMs) by modifying the identified CB2 inverse agonist XIE001. After designing, the reductive amination and coupling reactions were applied to yield sulfonamide and urea compounds. The [3H]CP55,940 and [35S]GTPγS binding assays demonstrated the potential NAM effects of compounds 1.7 and 2.4 out of 28 compounds. A further docking study indicated that compound 2.4 can bind to the predicted NAM binding site H with great affinity. In chapter 3, we designed and synthesized three analogs of putative CB2 AMs based on the known positive allosteric modulator (PAM) EC21a using an in-silico fragment-based scaffold hopping strategy. As identified by the [3H]CP55,940 binding experiment, three compounds, 3.3, 3.4, and 4.6 decreased the binding of CP55,940 with CB2R. Further functional assays will be done to investigate the biological effects of those molecules. In a word, this study demonstrates how potential CB2 AMs can be designed and synthesized. The novel AMs identified in this study may serve as leads for further optimization or as probes to characterize the AM binding pocket.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Yang, Boboy28@pitt.eduboy280009-0008-0759-7846
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorJun, Jadenjjj46@pitt.edujjj460000-0002-8585-7809
Committee ChairJun, Jadenjjj46@pitt.edujjj460000-0002-8585-7809
Committee MemberMcGuire, Terencetfm1@pitt.edutfm1
Committee MemberFeng, Zhiweizhf11@pitt.eduzhf11
Date: 3 May 2023
Date Type: Publication
Defense Date: 24 March 2023
Approval Date: 3 May 2023
Submission Date: 14 April 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 204
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: allosteric modulator, cannabinoid type two receptor
Date Deposited: 03 May 2023 13:43
Last Modified: 03 May 2023 13:43


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