Agonists full

The smallest sequence possessing most of the neurotensin spectmm of activities and its high potency is the hexapeptide C-terminus (1). [D-Trp ]-Neurotensin acts like a neurotensin antagonist in perfused heart preparations, but acts like a full agonist in guinea pig atria and rat stomach strips (122). 

The term intrinsic activity (ia) was defined as a measure of the abiUty of the dmg—receptor complex to generate response. When ia = 1, a full agonist is defined when ia = 0, an antagonist is defined. Thus, values 0 < ia < 1 define partial agonists as follows, where R is the response to dmg and R is the maximum response achieved. 

The more efficiently coupled is a given system the more likely agonists will produce the system maximum response (i.e., be full agonists). It can be shown also that if an... 

FIGURE 2.16 Effects of successive rectangular hyperbolae on receptor stimulus, (a) Stimulus to three agonists, (b) Three rectangular hyperbolic stimulus-response functions in series. Function 1 ((3 = 0.1) feeds function 2 ((3 = 0.03), which in turn feeds function 3 ((3 = 0.1). (c) Output from function 1. (d) Output from function 2 (functions 1 and 2 in series), (e) Final response output from function 3 (all three functions in series). Note how all three are full agonists when observed as final response. 

When the maximal stimulus-response capability of a given system is saturated by agonist stimulus, the agonist will be a full agonist (produce full system response). Not all full agonists are of equal efficacy they only all saturate the system. 

FIGURE 3.12 Dependence of constitutive receptor activity as ordinates (expressed as a percent of the maximal response to a full agonist for each receptor) versus magnitude of receptor expression (expressed as the amount of human cDNA used for transient transfection, logarithmic scale) in Xenopus laevis melanophores. Data shown for human chemokine CCR5 receptors (open circles), chemokine CXCR receptors (filled triangles), neuropeptide Y type 1 receptors (filled diamonds), neuropeptide Y type 2 receptors (open squares), and neuropeptide Y type 4 receptors (open inverted triangles). Data recalculated and redrawn from [27],... 

Binding experiments can yield direct measurements of ligand affinity (Chapter 4). However, with the use of null techniques these same estimates can also be obtained in functional studies. The concepts and procedures used to do this differ for partial and full agonists. 

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)... 

An example of the application of this method to the measurement of the affinity of the histamine receptor partial agonist E-2-P (with full agonist histamine) is shown in Figure 5.19. A full example of the application of this method for the measurement of partial agonists is given in Section 12.2.2. 

For full agonists, the approximation of the ECS0 as (5.10) affinity is not useful and other methods must be employed to estimate affinity. A method to measure the affinity of... 

The affinity of partial agonists can be made in functional experiments by the method of Barlow, Scott, and Stephenson [9] and for full agonists by the method of Furchgott [11],... 

It can be seen that as x, x > 1 then Max /Max—> 1 (i.e., both are full agonists). However, when the efficacy is low or when the stimulus-response coupling is inefficient (both conditions of low values for x), then x + 1 -> 1 and Max /Max = x7x (the relative maxima approximate the relative efficacy of the agonists). 

Schematically, response is produced by the full agonist ([AR]) complex—which interacts with the stimulus response system with equilibrium association constant Ke—and the partial agonist (lower efficacy), which interacts with an equilibrium association constant K ...

Therefore, there are two efficacies for the agonism one for the full agonist (denoted 1) and one for the partial agonist (denoted r ). In terms of the operational model for functional response, this leads to the following expression for response to a full agonist [A] in the presence of a partial agonist [B] (see Section 6.8.6) ... 

Another method to measure the affinity of a partial agonist has been presented by Stephenson [7] and modified by Kaumann and Marano [8], The method of Stephenson compares equiactive concentrations of full agonist in the absence of and the presence of a concentration of partial agonist to estimate the affinity of the partial agonist. The following equation is used (see Section 6.8.8) ... 

The pA2 calculation is derived by equating the response produced by the full agonist in the absence of the inverse agonist (Equation 6.64 with [B] = 0) to the response in the presence of a concentration of the inverse agonist that produces a dose ratio of 2 (by definition the pA2). For calculation of KB from 10-pAT... 

Comparing equiactive responses to the full agonist in the absence ([A]) and presence ([A7]) of the partial agonist (Responseap = Responsea) and rearranging yield... 

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