Antagonism mechanisms

The mechanism by which the methylxanthines produce CNS stimulation is not clearly estabUshed. These agents may function, ia part, to limit chloride channel activation ia a manner similar to that of pentylenetetra2ol (7) or hicuculline (8). Another possibiUty is a specific antagonism of the inhibitory neurotransmitter adenosiae [58-61-7] (19) (19). 

In some systems with truncated response observation times and utilizing slow acting antagonists a depression of the maximal response can be observed that is due to the kinetics of offset of the molecules and not a molecular mechanism of antagonism (hemi-equilibrium conditions). 

If the antagonism is insurmountable, then there are a number of molecular mechanisms possible. The next question to ask is if the maximal response to the agonist can be completely depressed to basal levels. If this is not the case, then there could be partial allosteric alteration of the signaling properties of the receptor. Alternatively, this could be due to a hemi-equilibrium condition that produces a partial shortfall to true competitive equilibrium, leading to incomplete depression of the maximal response but also antagonist concentration-related dextral displacement of the concentration response curve to the agonist (see Figure 10.19a). The model (see Section 10.6.5) used to fit these data is discussed in Section 6.5 and shown in... 

In cases where the plot of [A ]/Kd vs ICS0 is not linear, other mechanisms of antagonism may be operative. If there is a nearly vertical relationship, this be due to noncompetitive antagonism in a system with no receptor reserve (see Figure 12.2d). Alternatively, if the plot is linear at low values of [A ]/Kd and then approaches an asymptotic value the antagonism may be allosteric (the value of a defines the value of the asymptote) or noncompetitive in a system with receptor reserve (competitive shift until the maximal response is depressed, Figure 12.2d). 

Functional antagonism, reduction in the responsiveness to a given agonist by activation of cellular mechanisms that produce a counterstimulus to the cell. 

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