Partial agonists efficacy

Meptazinol is a high-efficacy partial agonist it also has central cholinergic activity which add to its analgesic effect. It is used to relieve acute or chronic pain of moderate intensity, e.g. postoperatively and in obstetrics. Meptazinol does not cause euphoria and withdrawal effects seem not to occur when it is discontinued. It appears not to induce a withdrawal syndrome in opioid-dependent subjets. 

BMY-7378 (63) and NAN-190 (64) were the first examples of LCAPs with antagonist actions (i.e., they are very low efficacy partial agonists) and WAY-100,635 (65) was the first example of a 5-HT "silent antagonist" (reviewed in Ref 214). 

If a compound is an antagonist, it does not mean it also doesn t have efficacy (partial agonists, inverse agonists). 

In contrast, ibogaine substituted as an interoceptive cue in mice trained to recognize MK-801 (dizocilpine) (119), but not to [(+)-HA-966] (a low-efficacy partial agonist of the glycine site at the NMDA receptor) (130) in a T-maze drug discrimination paradigm. 

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

It can be seen from Equation 5.7 that a more accurate estimate of the affinity will be obtained with partial agonists of low efficacy (i.e., as u v Vu o). Double reciprocal plots are known to produce... 

The relative efficacy of agonists can be estimated by measuring their relative maximal responses if those responses are considerably below the maximal response capability of the system (i.e., if they are both partial agonists producing <30 to 50% system maximal response). 

Maximal response of a partial agonist is dependent on efficacy (5.9.4)... 

Maximal Response of a Partial Agonist Is Dependent on Efficacy... 

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) ... 

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