GPR6 receptor: model construction, docking studies, drug design, and development of novel GPR6 modulators

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Israa Hani Isawi (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Patricia Reggio

Abstract: G protein coupled receptor 6 (GPR6) is a cannabinoid-related Class A GPCR orphan receptor, with high abundance in the central nervous system and high constitutive activation of adenylyl cyclase. A variety of research groups reported that GPR6 represents a possible target for the treatment of different neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, or Huntington’s Disease. Different pharmaceutical companies claim the use of GPR6 inverse agonists in the treatment of Parkinson’s disease and other dyskinesia syndromes by using a wide range of pyrazine derivatives analogs. In the first chapter, a review for the closely related orphan receptors GPR3/6/12, that share a high percentage of sequence homology is provided. This chapter includes background information about GPR3/6/12, pharmacological importance, reported molecules that target them, and their physiological role inside and outside the central nervous system. In sight of the lack of GPR6 structural information, the second chapter is a detailed description of constructing a homology model of the GPR6 inactive state (R), using a suite of computational techniques. Using the GPR6 R model, docking studies were performed to rationalize the structure activity relationship of the patented pyrazine analogs, that act as GPR6 inverse agonists. Chapter III discusses the designing, docking, and synthesis of novel potential GPR6 modulators. A subset of pyrazine analogs was used here as a starting point for the design of novel GPR6 inverse agonists using a fragment-based scaffold hopping approach, with taking into consideration the structural knowledge that has been gathered from building GPR6 model and docking studies. Chapter IV is focused on cannabimimetic compounds’ interaction with GPR6. Pharmacological evaluation and docking studies to help in understanding the structure activity relationship of cannabinoid receptor 2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide) and its analogs in regulating GPR6 Beta-arrestin2 recruitment is discussed in here. [This abstract has been edited to remove characters that will not display in this system. Please see the PDF for the full abstract.]

Additional Information

Language: English
Date: 2020
Cannabinoid, GPCR, GPR6, Molecular Dynamics, Molecular Modeling, Parkinson’s disease
Molecular dynamics
Molecules $x Models
Parkinson's disease $x Treatment

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