Agonist effect

FIGURE 8.14 Simulation for 5,000 theoretical ligands with calculated efficacy (Equation 8.11) and affinity (Equation 8.10). It can be seen that efficacy and affinity are correlated suggesting that all ligands that have been shown to bind to a receptor should be extensively tested for possible efficacy effects on the receptor directly, through agonist-effects on the receptor or changes in constitutive behavior of the receptor itself. Redrawn from [15]. 

In this case the modulator may alter both the affinity (through a) and efficacy (through ,) of the agonist effect on the receptor (see Section 7.4). The fractional receptor... 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

Function Pathways Effect of DA agonist Effect of DA antagonist Receptor... 

Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. The prime suspect is OMD which has a half-life of some 20 hours and reaches plasma concentrations three- to fourfold those of dopa. Suggestions that it may compete with dopa for entry across the blood-brain barrier or act as a partial agonist (effective antagonist) have not been substantiated experimentally although it does reduce DA release from rat striatal slices. Also if free radical production through deamination of DA is neurotoxic (see below) then this would be increased by levodopa. 

RESPONSE 1 have tended to think that things do not have affinity unless we see low nanomolar affinity. I think the EEG studies are fairly revealing in that regard. The fact that we see this increase in alpha-1 power in the striatum is a characteristic of 5-HT2 agonists. And we are clearly seeing EEG effects at doses that are not increasing that power in the alpha-1 frequency. 1 tend to think that 5-HT2 agonist effects are not that important in the action of these compounds. 

In addition to the aetions of MDMA and other derivatives at 5-HT2 serotonin reeeptors. some of the effeets on serotonergic systems could be mediated via S-HTja reeeptors, at whieh MDMA has a moderate affinity. Direct agonist effects at this site might eontribute to the mood-altering and calming effects of the drug, sinee similar effects have been reported for novel anxiolyties sueh as ipsaperone and buspirone, which interact with 5-HTia serotonin reeeptors. 

Another mechanism to maintain CO when contractility is low is to increase heart rate. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on P-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function. 

Dobutamine is a /Jj- and / -receptor agonist with some oq-agonist effects. The net vascular effect is usually vasodilation. It has a potent inotropic effect without producing a significant change in heart rate. Initial doses of 2.5 to 5 mcg/kg/min can be increased progressively to 20 mcg/kg/min on the basis of clinical and hemodynamic responses. 

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