Receptor signaling allosteric modulators

Current treatment for insomnia centers on GABAa ( aminobutyric acid) receptor signalling and includes GABAa receptor positive allosteric modulators (PAMs), for example, agents such as zolpidem (Ambien, 2). While zolpidem has been off patent since 2007, another similar compound, eszopiclone (Lunesta, 3), is still prescribed for insomnia, with sales in 2010 reaching almost 1 biUion. These compounds are classified as sedative-hypnotics and their side effecTs include cognitive impairment, musculoskeletal impairment, and mild dysphoria. ... 

The receptor can bind both the probe (agonist, radioligand, [A]) and allosteric modulator ([B]). The agonist (7.11) bound receptor signal through the normal operational model ([AR] complex interacting with cellular stimulus-response machinery with association constant Ke) and in a possibly different manner when the allosteric modulator is bound (complex [ABR] interacting with cell with... 

Thus, the non-zero , term reduces the effect of a on the pA2 estimate. It can be seen that when receptor signaling is blocked by the allosteric modulator ( = 0), Equation 7.34 reduces to Equation 7.32. 

Used to estimate system independent potency of an allosteric modulator that affects the affinity of the agonist for the receptor but does not affect receptor signaling capability. 

FIGURE 10.19 Patterns of insurmountable blockade of receptors under conditions of (a) hemi-equilibria and (b) allosteric modulation by a modulator that only partially reduces receptor signaling, (a) Concentration-response curves to the full agonist are shifted to the right in a concentration-dependent manner. The maximal response is partially depressed and may attain a plateau level, (b) Curves are shifted to a limiting value characteristic of saturable allosteric modulation. In addition, the maximal response is depressed to a new asymptote. Note that the maximal response is not blocked to basal levels indicative of >0 (see Section 7.8.2 and Equation 7.3). 

In all cases, the molar concentration at which blockade of an agonist response is first encountered is a reasonable indication of the molecular potency of the antagonist, with the possible exception being allosteric modulators that block receptor signaling but increase the affinity of the receptor for the agonist. 

It can be seen from this example that the inhibition curve shifts to the left with increasing concentration of agonist, indicating an allosteric mechanism whereby the modulator blocks receptor signaling but increases the affinity of the receptor for the agonist. 

Noetzel MJ, Gregory KJ, Vinson PN, Manka JT, Stauffer SR, Lindsley CW et al (2013) A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Mol Pharmacol 83 835-847... 

Mitsukawa K, Yamamoto R, Ofner S et al (2005) A selective metabotropic glutamate receptor 7 agonist activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc Natl Acad Sci USA 102 18712-18717... 

Kenakin, T. P. (2010). G protein coupled receptors as allosteric proteins and the role of allosteric modulators. Joumfl/ of Receptor and Signal Transduction Research, 30, 313-321. 

Bemat, V., Brox, R., Heinrich, M. R., Auberson, Y. P., Tschammer, N. (2015). Ligand-biased and probe-dependent modulation of chemokine receptor CXCR3 signaling by negative allosteric modulators. ChemMedChem, 10(3), 566—574. http //dx.doi.org/ 10.1002/cmdc.201402507. 

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