Receptors reserve

Fig. 8. Agonist, dose—response curves, (a) For an agonist where a value of 10 M is indicated at the concentration giving 50% response, (b) For an agonist alone, Aq, and in the presence of increasing amounts of irreversible receptor antagonists, B—F. There is a progressive rightward shift of the dose—response curve prior to reduction of maximum response. This pattern is consistent with the presence of a receptor reserve.

Receptor reserve is a property of the tissue (i.e., the strength of amplification of receptor stimulus inherent to the cells) and it is a property of the agonist (i.e., how much stimulus is imparted to the system by a given agonist receptor occupancy). This latter factor is quantified as the efficacy of the agonist. A high-efficacy agonist need occupy a smaller fraction of the receptor population than a... 

In cases where there is a substantial receptor reserve such that there is a measurable dextral displacement of the concentration response curves, then another reliable method for determining the affinity of the noncompetitive antagonist is to measure the pA2 (—log of the molar concentration that produces a twofold shift to the right of the agonist concentration-response curve). It can be shown that for purely noncompetitive antagonists the pA2 is related to the pKB with the relation (see Section 6.8.10)... 

As with insurmountable orthos ter ic antagonists (see Section 6.4), in systems with a receptor reserve for the... 

If there is no receptor reserve for the system, then an insurmountable antagonist, whether allosteric or orthosteric, will produce immediate depression of the agonist concentration-response curve with no concomitant shift to the right. Under these circumstances,... 

Noncompetitive Antagonism in Systems with Receptor Reserve... 

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). 

Spare receptors, another term for receptor reserve (see Receptor reserve). 

A consequence of a very large receptor reserve for CB1 receptors would be that PET or SPECT could not be used to image the occupancy of the CB1 receptor by biologically significant doses of agonist drugs. This is... 

Gifford AN, Bruneus M, Gatley SJ, Lan R, Makriyannis A, Volkow ND. Large receptor reserve for cannabinoid actions in the central nervous system. J Pharmacol Exp Ther 1999 2 478-483. 

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