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Design, Synthesis, and Structure Validation of Sultam Analogs as Potential Allosteric Modulators of Cannabinoid Receptor Subtype 2 (CB2)

Lu, Mengyao (2024) Design, Synthesis, and Structure Validation of Sultam Analogs as Potential Allosteric Modulators of Cannabinoid Receptor Subtype 2 (CB2). Master's Thesis, University of Pittsburgh. (Unpublished)

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The cannabinoid 2 (CB2) receptor is a class A GPCR in the endocannabinoid system. It is a promising target for treating neurodegenerative diseases, immune disorders, and neuropathic pain. CB2 receptors are highly distributed in the immune system and less abundant in CNS compared to its homologous subtype CB1. The adverse effects of CB1 ligands can be avoided by selectively targeting CB2. Allosteric modulators (AMs) can help achieve the selectivity between the subtypes by binding to less conserved allosteric binding sites. Moreover, developing allosteric modulators can lower the risk of overdosing and side effects caused by other downstream signaling. There is only one reported novel synthetic small molecule that acts as a CB2 positive allosteric modulator (PAM) and derivates of natural products as a negative allosteric modulator (NAM). We designed and synthesized a series of sultam compounds to develop potential CB2 allosteric modulators based on existing CB2 PAM, EC21a. As an initial study, we performed the docking study to verify the affinity of our newly designed sultams at the potential allosteric binding site. Our novel sultam compounds can be synthesized through multiple steps, including methylation using methane sulfonyl chloride, benzylation on the nitrogen, Dieckmann-like cyclization to construct the sultam ring, and isocyanate coupling reaction to afford diverse sultams with different substituents on the rings. The final sultam compounds were purified using flash column chromatography and trituration, and their purity was measured by HPLC and LC/MS. After that, we verified all compound structures using 1H and 13C NMR. The X-ray data shows the amide-bond orientation of the sultam compound. Using a cAMP function assay, we identified 4.2 as a potential CB2 NAM compound.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lu, Mengyao18962458599@163.commel286
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMcGuire, Terencetfm1@pitt.eduTFM1
Committee MemberFeng, Zhiweizhf11@pitt.eduzhf11
Committee MemberXie, Xiang-Qunxix15@pitt.eduxix15
Thesis AdvisorJun, JadenJJJ46@pitt.edujjj46
Date: 2 May 2024
Date Type: Publication
Defense Date: 27 May 2024
Approval Date: 2 May 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: 133
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: ECS
Date Deposited: 02 May 2024 15:06
Last Modified: 02 May 2024 15:06


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