Receptor allosteric modulation

Leach K, Loiacono RE, Felder CC, McKinzie DL, Mogg A, Shaw DB, Sexton PM, Christopoulos A (2010) Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties. Neuropsychol Pharmacol 35 855-869... 

Ferguson GN, Valant C, Home J et al (2008) 2-Aminothienopyridazines as novel adenosine Al receptor allosteric modulators and antagonists. J Med Chem 51 6165-6172... 

Fernandez MC, Castano A, Dominguez E et al (2006) A novel class of AMPA receptor allosteric modulators. Part 1 design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives. Bioorg Med Chem Lett 16 5057-5061... 

Differential effects of the allosteric modulator alcuronium on various probes for the m2 muscarinic receptor. 

FIGURE 4.13 Effect of the allosteric modulator 5-(N-ethyl-N-isopropyl)-amyloride (EPA) on the kinetics dissociation of [3H] yohimbine from c/j-adrenoceptors, (a) Receptor occupancy of [3H] yohimbine with time in the absence (filled circles) and presence (open circles) of EPA 0.03 mM, 0.1 mM (filled triangles), 0.3 mM (open squares), 1 mM (filled squares), and 3 mM (open triangles), (b) Regression of observed rate constant for offset of concentration of [3H] yohimbine in the presence of various concentrations of EPA on concentrations of EPA (abscissae in mM on a logarithmic scale). Data redrawn from [13]. 

FIGURE 7.5 Schematic diagram of a GPCR in a native conformation (black) and alios terically altered conformation (red). When these are superimposed upon each other it can be seen that more than one region of the receptor is altered upon allosteric modulation (see circled areas). 

FIGURE 7.7 Effect of the allosteric modulator ebumamonine on the potency of muscarinic agonists on m2 receptors. It can be seen that while no change in potency is observed for APE (arecaidine propargyl ester) pilocarpine is antagonized and arecoline is potentiated, illustrating the probe dependence of allosterism. From [1],... 

The effects of different allosteric modulators oil common agonists of muscarinic receptors. 

AR] complex) interacts with an equilibrium association constant Ke (to yield an efficacy term x) and the allosterically altered agonist-bound receptor complex ([ABR] complex) interacts with the cell with equilibrium association constant K e (to yield an altered efficacy x7). It is useful to define a ratio of efficacies for the native and allosterically modulated receptor of x /x (denoted , where = x//x). 

The response to an agonist in the presence of an allosteric modulator that can alter the affinity and efficacy of the receptor is given by (see Section 7.8.2)... 

FIGURE 7.14 Effect of an allosteric modulator that increases the efficacy of the agonist but has no effect on affinity in two different systems, (a) For full agonists, increases in efficacy produce parallel shifts to the left of the concentration-response curves. Responses modeled with Equation 7.3 with a= 1, , = 5, t = 20, and Ka = 3j.lM. Curves shown for [B]/Kb = 0, 0.3, 1, 3, 10, and 30. (b) In systems with lower receptor density and/or poorer receptor coupling where the agonists does not produce the full system maximal response, an allosteric modulator increases the maximal response and shifts the curves to the left. Responses modeled with Equation 7.3 for the same agonist and same allosteric modulator but in a different tissue (parameters as for A except t= 1). 

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