Identification of full, partial and inverse CC chemokine receptor 3 agonists using [35S]GTPγS binding

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

“…31,32 CCR3 is expressed by eosinophils, Th2 cell subsets, basophils, mast cells, neural tissue, some epithelia, and CD34 ϩ progenitor cells. 33,34 Eosinophil chemotaxis induced by the most potent CCR3 agonists, such as eotaxin and macrophage chemoattractant protein 4 (MCP-4), can be inhibited by CCL18 at concentrations as low as 10 nM.…”

“…33,34 Eosinophil chemotaxis induced by the most potent CCR3 agonists, such as eotaxin and macrophage chemoattractant protein 4 (MCP-4), can be inhibited by CCL18 at concentrations as low as 10 nM. 31,32 The CCL18 plasma levels in symptomatic Gaucher patients exceed these inhibitory concentrations considerably (3-27 times). It seems likely that tissues rich in Gaucher cells contain even higher CCL18 concentrations.…”

An Overall Picture of Chemokine Receptors: Basic Research and Drug Development

“…It proves to be a high signal to noise assay and could be tolerated to 1% DMSO. Moreover, it can be used to discriminate full, partial and inverse agonist [13,94], which is very important to drug development because agonist of chemokines receptors may have more side effects when used for treatment.…”

“…However, GPCRs can be endowed with agonist independent activity (constitutively activity) by mutations that release the constraints in receptor or form new interactions in the receptor to maintain its R* state [95]. Moreover, some GPCRs can get detectable signals in vivo or by overexpression because they have a large percent R* state naturally [94,95]. Constitutively active GPCRs are very useful tool in drug screening because they have the following advantages: 1) they can be applied to discriminate agonist, partial agonist and inverse agonist because their signals can go two ways, that is, increasing the basal activity by agonist and decreasing the basal activity by inverse agonists [13,94,95]; 2) because most of constitutively active receptors are more sensitive to stimuli, it is possible to get the low activity ligands that might be missed when using wild type receptors; 3) they can be used for screening out agonists and inverse agonists even for orphan GPCRs.…”

“…Moreover, some GPCRs can get detectable signals in vivo or by overexpression because they have a large percent R* state naturally [94,95]. Constitutively active GPCRs are very useful tool in drug screening because they have the following advantages: 1) they can be applied to discriminate agonist, partial agonist and inverse agonist because their signals can go two ways, that is, increasing the basal activity by agonist and decreasing the basal activity by inverse agonists [13,94,95]; 2) because most of constitutively active receptors are more sensitive to stimuli, it is possible to get the low activity ligands that might be missed when using wild type receptors; 3) they can be used for screening out agonists and inverse agonists even for orphan GPCRs. In turn, these ligands will be good tools to discover the function of orphan GPCRs in vivo [95]; 4) it will save money when the agonists for the receptor are expensive, for example, chemokines.…”