Review of Recent Developments of Cb2 Selective Agonists and Lead Optimization and Molecular Docking Studies of Gpr55 Selective Agonists
Year: 2013
Type: dissertation
Abstract: This study consists of two Parts; the literature section of the thesis is focused on the review of recent development of selective agonists for the cannabinoid CB2 receptor.The experimental part is focused on the optimization and molecular docking studies of GPR55 lead compound.CB2 selective agonists have been revealed to have improved therapeutic effects without CNS side effects at doses within the therapeutic window.They have been implicated to be good targets in novel drug discovery for osteoarthritic pain, neuropathic pain, post-surgical pain, and cancer just to mention a few.In this first part of the study, review of the latest advances made in the development of CB2 cannabinoid selective agonists and chemical scaffolds is made for scientific materials that appeared from 2010 to early 2013.It was observed that a lot of work has been done in recent years on CB2 with notable improvement in ligands with high selectivity and affinity with the receptor.The second part of the study was about the optimization of a GPR55 lead compound for improved affinity, activity, selectivity and potency.Researches have revealed the therapeutic potential of GPR55 as a novel target for the treatment of inflammation, pain, and cancer.It is also important in bone physiology and remodeling.Recent evidence suggests a possible therapeutic use of GPR55 ligands for a novel drug discovery.In the synthetic part, varying primary amines were reacted with either 4-nitrobenzenesulfonyl chloride or 4-nitrophenyl chloroformate to displace the chlorine group.The nitro moiety was converted to an amine group and the resulting compound is then coupled to 1,1-biphenyl-4-carbonyl isothiocyanate 69.Yields were relatively high in the first steps of the synthesis ranging from 38% to100%.The coupling step was relatively slow with yields ranging from 5% to 100%.A molecular docking study was done on the produced ligands on GPR55 homology model using Molecular Operating Environment suite (MOE) and Schrödinger suite of software.The studied ligands had high degree of interactions with pocket residues, the GPR55 ligands are hope to have improved affinity and selectivity for the GPR55 receptor.An in vitro study on the produced ligands in CB1 and CB2 models showed no recordable activity in these media.Any recordable activity in the in vitro testing of the ligands in GPR55 model will go further to prove the selective nature of our produced compounds.
Author: Frank Adusei‐Mensah
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Itä-Suomen Yliopisto
OpenAlex ID: W2188112483