Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SELECTIVE CANNABINOID RECEPTOR 2 (CB2) LIGANDS WITH THERAPEUTIC POTENTIALS

Almehizia, Abdulrahman (2015) DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL SELECTIVE CANNABINOID RECEPTOR 2 (CB2) LIGANDS WITH THERAPEUTIC POTENTIALS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Primary Text
Restricted to University of Pittsburgh users only until 7 April 2020.

Download (5MB) | Request a Copy

Abstract

Cannabinoid receptors 1 and 2 (CB1 and CB2) belong to the rhodopsin-like family of the G-Protein Coupled Receptors (GPCRs). CB1 receptors are highly expressed in the central nervous system, while CB2 receptors are expressed mainly in the immune cells and the periphery. Targeting the CB2 receptors is believed to avoid the psychoactive side effects associated with CB1 receptors. CB2 receptors have been shown to be involved in several physiological functions as well as diseases, such as pain, multiple sclerosis, osteoporosis, and cancer demonstrating the importance of the CB2 receptors. In the present study, we employed chemistry design and discovery to identify novel CB2 ligands, carried out in-vitro functional studies, and evaluated the therapeutic potentials.
Several chemical scaffolds were discovered and evaluated. The di-amide scaffold was discovered utilizing pharmacophore drug discovery and molecular docking studies. Several derivatives of the di-amide scaffold demonstrated potent and highly selective CB2 inverse agonists as well as potent anti-osteoclast formation capabilities. The di-amide derivatives suffered from weak anti-multiple myeloma (MM) properties and poor pharmacokinetic properties. A new scaffold was identified utilizing scaffold hopping and molecular docking studies. However, the 2-(sulfonylamino)-2-phenylacetamide scaffold demonstrated weak CB2 binding affinity. Due to the limitation of the two previous scaffolds, virtual high-throughput screening as well as structure-based drug design were utilized for scaffold hopping in order to identify new CB2 scaffolds. A new lead compound was identified and structure activity relationship (SAR) studies were conducted on the scaffold 4-(aminomethyl)-N,N-diethylaniline. Several novel compounds were discovered with high potency and selectivity. Functional experiments showed different functionality (agonist and inverse agonist) of these compounds. Nevertheless, therapeutic studies showed that inverse agonism is essential for the OCL inhibition effects while anti-MM experiments showed that CB2 agonists are more effective than inverse agonists.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Almehizia, Abdulrahmanaba30@pitt.eduABA30
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorXie, Xiang-Qunxix15@pitt.eduXIX15
Committee MemberSchiff, Paul pschiff@pitt.eduPSCHIFF
Committee MemberVollmer, Regis R.vollm@pitt.eduVOLLM
Committee MemberFloreancig, Paul Eflorean@pitt.eduFLOREAN
Committee MemberWang, Lirongliw30@pitt.eduLIW30
Date: 7 April 2015
Date Type: Publication
Defense Date: 17 March 2015
Approval Date: 7 April 2015
Submission Date: 6 April 2015
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 331
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cannabinoid CB2 Myeloma Osteoporosis OCL Formation
Date Deposited: 07 Apr 2015 17:48
Last Modified: 15 Nov 2016 14:26
URI: http://d-scholarship.pitt.edu/id/eprint/24142

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item