Negative allosteric modulation

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

An example of negative allosteric modulation is the case of the antidepressants, which act as neurotransmitter reuptake blockers for the neurotransmitters norepinephrine and serotonin. This has already been discussed in Chapter 2. When the neurotransmitters norepinephrine and serotonin bind to their own selective receptor sites, they are normally transported back into the presynaptic neuron, as shown in Figure 2-23- Thus the empty reuptake carrier (Fig. 2—20) binds to the neurotransmitter (Fig. 2—21) to begin the transport process (Fig. 2—23). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter (represented as an icon in Figs. 2—22 and 2—24), this causes the neurotransmitter to no longer be able to bind there, thereby blocking synaptic re-... 

To understand both positive allosteric modulation and negative allosteric modulation. 

Ruel J., Guitton M. J., and Puell J. L. (2002). Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist. CNS Drug Rev. 8 235-254. 

Relationship between the initial velocity (v) of aspartate transcarbamoylase and the substrate concentration. Note that ATP is a positive allosteric modulator, which causes decreased 8 0.5, whereas CTP is a negative allosteric modulator, which causes increased Ko. ... 

FIGURE 3.7 Plots of fractional orthosteric Ugand-receptor occupancy as a function of log [orthosteric ligand concentration]. Curves shifts induced by a competitive antagonist (a) or a negative allosteric modulator (b). Note the limits in curve shifts with an allosteric modulator (ceiling effect). 

A finding that abnormal- cannabidiol and cannabidiol can attenuate phenylephrine-induced contractions of the mouse isolated vas deferens points to the presence of abnormal-cannabidiol-sensitive receptors in the smooth muscle cells of this tissue (Pertwee et al. 2002 Thomas et al. 2004). Cannabidiol also decreases meflioxamine and noradrenaline-induced contractions of the mouse vas deferens and antagonizes phenylephrine and noradrenahne in an insurmountable manner (Pertwee et al. 2002). It may be, therefore, that cannabidiol, and possibly also abnormal-cannabidiol, are negative allosteric modulators of the a 1 -adrenoceptor. 

Fig. 11 Negative allosteric modulators (non-MPEP-based) of mGluR5...

Macchiarulo A, De Luca L, Costantino G et al (2004) QSAR study of anticonvulsant negative allosteric modulators of the AMPA receptor. J Med Chem 47 1860-1863... 

Lindsley CW, Emmitte KA (2009) Recent progress in the discovery and development of negative allosteric modulators of mGluR5. Curr Opin Drug Discov Dev 12 446-457... 

Figure 10 Effects of ligands with different modes of action on an agonist-induced response. By comparing the level of inhibition at full receptor occupancy with the baseline, a distinction can be made between an orthosteric antagonist (ortho anta), orthosteric inverse agonist (ortho inv ago), negative allosteric modulator (NAM), and positive allosteric modulator (PAM).

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. 

Isothiazole has been incorporated into an orally efficacious, negative allosteric modulator 119 for mGlu5 receptor (metabotropic glutamate receptor 5) (13BMCL1249) and sultam into ADAMTS-5 (aggrecanase-2) inhibitor 120 (13BMCL2111). 

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