Receptor promiscuity

Chemokines exhibit complex ligand-receptor relationships. Often, individual chemokines can bind productively to more than one receptor, and many chemokine receptors can signal in response to more than one chemokine. Usually, these chemokine receptors bind multiple chemokines within the same subfamily. The best documented example of chemokine receptor promiscuity across subfamilies involves CXCR3 binding to CCL21. 

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Smirlis D, Muangmoonchai R, Edwards M, et al. Orphan receptor promiscuity in the induction of cytochromes P450 hy xenohiotics. J Biol Chem 2001 276 ... 

Numbers refer to the population of molecules containing each scaffold in the respective sets. The figures in parentheses give the level of nuclear receptor promiscuity associated to scaffolds in the NRactive set. 

Kenakin, T., 1995. Agonist-receptor efficacy I. Mechanisms of efficacy and receptor promiscuity. Trends Pharmacol. Sci. 16, 188-192. 

Lipophilicity is a key drug-like attribute and is important for desolvation and binding to drug protein targets. It is not surprising therefore, that high lipophilicity may be responsible for off-target receptor promiscuity and subsequent... 

AZ receptor promiscuity Maximize LLE = pICso — logP to reduce promiscuity [3]... 

Potassium Competitive Acid Blockers The pregnane X receptor (PXR) is a promiscuous nuclear receptor, that has evolved to protect the body from toxic chemicals. It is activated by a wide variety of xenobiotics including several diugs like rifampicin, hyperforin ( the active ingredient of St. John s wort), clotrimazole and others. PXR heterodimerizes with the... 

TM) GPCRs, and the identification of these two molecules facilitated the discovery of many of the other chemokine receptors. The identification of the two IL8 receptors was followed, shortly after, by the cloning of a receptor for CC chemokines. This receptor was initially called CC-CKR1 (now CCR1) and was shown to promiscuously bind a number of members of the CC chemokine family (6). Subsequent to the identification of these three chemokine receptors, two principal methods have been used to clone the cDNAs for the other currently identified receptors ... 

Note PI3K assays will vary according to the type of T-cell model employed and concentration of chemokine assayed. For clarity, activation of PI3K by chemokines that show promiscuity toward receptors is attributed to signaling via all the receptors bound by these ligands, even though such details have not necessarily been investigated. 

CCR1 is a promiscuous chemokine receptor bound by several chemokines, such as MIP-la/CCL3, MIP-lp/CCL4, and RANTES/CCL5 (25-28). Although these chemokines are generally known to attract monocytes but not neutrophils in vitro (29), a previous report indicated that human MIP-la but not MIP-ip, could induce a small but detectable level of calcium flux in human neutrophils (30). When recombinant human MIP-la was injected into human skin to examine the in vivo role of this chemokine, rapid infiltration of neutrophils was observed prior to the appearance of other cell types, such as monocytes and lymphocytes (31). 

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