Abstract
Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R; OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among the GPCRs, CX3CR1 is focused as target of PET during inflammation of brain and spinal cord.
Highlights
Targeting 7TM receptors or G protein-coupled receptors (GPCR) belongs to the most successful pharmacological concepts in development of therapeutics with non-antibiotic clinical applications [1] [2] [3]
This contribution compares small-molecule lead structures disclosed during the last decade as potential receptor ligands and possible approaches for development of pharmacophores with focus on neuropeptide Y1 (NPY1) and 2 receptors, orexin 1 and 2 receptors, corticotropin releasing factor receptor 1 (CRFR1) and the chemokine receptor CX3CR1 as well as the possibilities suggested by new recognitions and challenges on cellular subtypes and their distributions in brain and spinal cord [62]
The results showed high levels of receptor mRNA in microglia cells compared to neurons and astrocytes while fractalkine mRNA was very high in neurons in comparison to astrocytes and microglia [17]
Summary
Targeting 7TM receptors or G protein-coupled receptors (GPCR) belongs to the most successful pharmacological concepts in development of therapeutics with non-antibiotic clinical applications [1] [2] [3]. Other interesting fields are the presence of microglia in neurogenic niches, the possibilities of transformation of brain cells and opportunities of support of tissue repair by transplantation of microglia in selected brain regions or spinal cord [33] [34] [35]. It is not clear if the dogma is true that microglia population of the brain recruits new cells only from itself. Different histological fingerprints have been shown for cerebral and cerebellar microglia [45] and it is presumed that potential tracers can better achieve cellular populations of the spinal cord than of the brain due to differences between blood brain barrier (BBB) and blood spinal cord barrier (BSCB) [46]
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