Constitutively Active Receptors and Inverse Agonists

FIGURE 1.11 A model to show the influence of a ligand, L, on the equilibrium between the active and inactive forms of a constitutively active receptor, R. Note that if L, R, and LR are in equilibrium, and likewise L, R and LR, then the same must hold for LR and LR (see Appendix 1.6B (Section 1.6.7.2) for further explanation). 

Suppose that L combines only with the inactive, R, form. Then the presence of L, by promoting the formation of LR at the expense of the other species, will reduce the proportion of receptors in the active, R, state. L is said to be an inverse agonist or negative antagonist and to possess negative efficacy. If, in contrast, L combines with the R form alone, it will act as a conventional or positive agonist of very high intrinsic efficacy. 

Exploring the scheme further, a partial agonist will bind to both R and R but with some preferential affinity for one or the other of the two states. If the preference is for R, the ligand will be a partial inverse agonist, as its presence will reduce the number of receptors in the active state, though not to zero. 

Such a ligand, however, will reduce the action of either a conventional or an inverse agonist, and so in effect is an antagonist. More precisely, it is a neutral competitive antagonist. If large 

FIGURE 1.12 The relationship between the total fraction of receptors in the active state (pR + pAR,) and ligand concentration ([L]) for a constitutively active receptor. The curve has been drawn according to Eq. (1.39), using the following values E0 = 0.2, Kh = 200 nM, a = KJK = 0.1, 1, and 100, as shown. Note that on this model some of the receptors (a fraction given by /( 1 + E0) = 0.167) are active in the absence of ligand. 

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