Agonist model

Schematic representation of a) pharmacophore elements as defined in various 5-HTiA agonist models [34, 36, 38] and b) the binding site of agonists like serotonin and 8-OH-DPAT in the 5-HT1A receptor model by Kuipers et al. [52].

Modeling and Crystallographic Studies of Estrogen Agonists and Antagonists... 

Fig. 2. Molecular modeling of dopamine D2 receptor agonists used to define the molecular conformation needed for selective high affinity binding.

There are even receptors that are known to become activated only due to interaction with a synthetic chemical, and no physiological agonist for such a receptor has been characterized. A model receptor in this class is the so-called Ah receptor complex that becomes activated subsequent to its exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxiu (TCDD). Activation of the. Ah receptor... 

Very recently, a very bold chemical model for histamine H2-receptors has been proposed using [18]aneN6-3H+ 84), which can chemically recognize histamine, histamine H2-agonists, and histamine H2-antagonists such as cimetidine XII or ranitidine XIII that are currently in world-wide use for treatment of peptic ulcers 85). 

It can be seen that efficacy in this model is both an agonist and a tissue-specific term. Furchgott [9] separated the tissue... 

Black and Leff [11] presented a model, termed the operational model, that avoids the inclusion of ad hoc terms for efficacy. This model is based on the experimental observation that the relationship between agonist concentration and tissue response is most often hyperbolic. This allows for response to be expressed in terms of... 

FIGURE 3.7 Principal components of the operational model. The 3D array defines processes of receptor occupation (plane 1), the transduction of the agonist occupancy into response (plane 2) in defining the relationship between agonist concentration, and tissue response (plane 3). The term a refers to the intrinsic activity of the agonist. 

FIGURE 3.6 Classical model of agonism. Ordinates response as a fraction of the system maximal response. Abscissae logarithms of molar concentrations of agonist, (a) Effect of changing efficacy as defined by Stephenson [24], Stimulus-response coupling defined by hyperbolic function Response = stimulus/(stimulus-F 0.1). (b) Dose-response curves for agonist of e = 1 and various values for Ka. 

The resulting modification is called the extended ternary complex model [3], which describes the spontaneous formation of active state receptor ([Ra]) from an inactive state receptor ([RJ) according to an allosteric constant (L = [Ra]/[RJ). The active state receptor can form a complex with G-protein ([G]) spontaneously to form RaG, or agonist activation can induce formation of a ternary complex ARaG ... 

While the extended ternary complex model accounts for the presence of constitutive receptor activity in the absence of ligands, it is thermodynamically incomplete from the standpoint of the interaction of receptor and G-protein species. Specifically, it must be possible from a thermodynamic point of view for the inactive state receptor (ligand bound and unbound) to interact with G-proteins. The cubic ternary complex model accommodates this possibility [23-25]. From a practical point of view, it allows for the potential of receptors (whether unbound or bound by inverse agonists) to sequester G-proteins into a nonsignaling state. 

There are some specific differences between the cubic and extended ternary complex models in terms of predictions of system and drug behavior. The first is that the receptor, either ligand bound or not bound, can form a complex with the G-protein and that this complex need not signal (i.e., [ARiG] and [RjG]). Under these circumstances an inverse agonist (one that stabilizes the inactive state of the receptor) theoretically can form inactive ternary complexes and thus sequester G-proteins away from signaling pathways. There is evidence that this can occur with cannabi-noid receptor [26]. The cubic ternary complex model also... 

The basis of this model is the experimental fact that most agonist dose-response curves are hyperbolic in nature. The reasoning for making this assumption is as follows. If agonist binding is governed by mass action, then the relationship between the agonist-receptor complex and response must either be linear or hyperbolic as well. Response is thus defined as... 

The extended ternary complex model [23] was conceived after it was clear that receptors could spontaneously activate G-proteins in the absence of agonist. It is an amalgam of the ternary complex model [12] and two-state theory that allows proteins to spontaneously exist in two conformations, each having different properties with respect to other proteins and to ligands. Thus, two receptor species are described [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These coexist according to an allosteric constant (L = [Ra]/[Ri]) ... 

DeLean, A., Stadel, J. M. Lefkowitz, R. J. (1980). A ternary complex model explains the agonist-specific binding properties... 

Receptor density has disparate effects on the potency and maximal responses to agonists. The operational model predicts that the EC50 to an agonist will vary with receptor density according to the following relationship (see Section 3.13.3)... 

Dose-response curves to a full agonist [A] and a partial agonist [P] are obtained in the same receptor preparation. From these curves, reciprocals of equiactive concentrations of the full and partial agonist are used in the following linear equation (derived for the operational model see Section 5.9.2)... 

The response to an agonist [A] in terms of the classical model is given as a function of stimulus, which is... 

In systems of extremely poor receptor coupling, (3 will be a large value and e e /e (the relative maximal response approximates the relative efficacy of the agonists). In terms of the operational model, response is given by... 

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