Abstract
G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.
Highlights
GPCRs as Drug TargetsThe G protein-coupled receptors (GPCRs) are highly conserved and ubiquitously expressed in the cellular membrane of eukaryotes
Oral administration of this retinoid to retinal pigment epithelium-specific protein 65 (RPE65)-/- or lecithin retinol acyltransferase (LRAT)-/- mice led to the formation of isorhodopsin, detected by UV-vis spectroscopy in the protein sample purified from the rod outer segment (OS) membranes isolated from mouse eyes, and restored visual function, as determined by electroretinography (ERG)
Continuous development of drugs targeting GPCRs related to various pathologies, including psychiatric disorders, diabetes, thrombosis, Alzheimer’s, and eye-related impairments resulted in a significant increase of drug candidates evaluated in clinical trials in recent years
Summary
The G protein-coupled receptors (GPCRs) are highly conserved and ubiquitously expressed in the cellular membrane of eukaryotes. GPCRs provide ways for cells to sense and respond to their external environments through various ligands such as neurotransmitters, peptides, lipids, amino acids, nucleotides, light, and odorants. These receptors are involved in maintaining the organism’s homeostasis by regulating a plethora of physiological processes [1]. Pharmacological modulation of more than 56% of GPCRs remains largely unexplored mostly due to their complex pharmacology and limited experimental tools that constrict the satisfactory progress of this research area Knowing that these not-targeted GPCRs could be associated with pathologies stresses the necessity of advanced screening and identification of novel GPCR ligands [3,5,6]. Understanding the complex pharmacology of GPCRs is of great interest to biology in general and pharmaceutical industry in particular
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
