Effects of agonists

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

Naloxone is a pure opioid antagonist that binds competitively to opioid receptors but does not produce an analgesic response. It is used to reverse the toxic effects of agonist and agonist-antagonist opioids. 

Antagonists (A) attenuate the effect of agonists, that is, their action is anti-agonistic . 

The effects of agonists and inverse agonists do not represent two distinct states but rather the ends of a spectrum of activity. Compounds that have less... 

Preston, K.L. and Bigelow, G.E., Effects of agonist-antagonist opioids in humans trained in a hydro-morphone/not hydromorphone discrimination, J. Pharmacol. Exp. Ther., 295, 114, 2000. 

The opioid antagonists bind with high affinity to opioid receptors but fail to activate the receptor-mediated response. Administration of opioid antagonists produces no profound effects in normal individuals. However, in patients addicted to opioids, antagonists rapidly reverse the effect of agonists, such as heroin, and precipitate the symptoms of opiate withdrawal. 

Fig. 8. Effects of agonists on cytosolic Ca2+ (measured by fluorescence) in isolated rat hepatocytes loaded with Quin 2. The concentrations of agonists are Epi, 1 /uM epinephrine Phenyl, 10 fiM phenylephrine Vaso, 10 nM vasopressin Glue, 10 nM glucagon. Reproduced from Ref. 3 by permission of the authors and publisher.

Sometimes, the target protein itself will respond to the binding of antibodies with some cytotoxic effect. You have probably heard about apoptosis (programmed cell death). This is triggered by specific cell surface receptors, and some antibodies can mimic the effect of agonists at these receptors. 

Adenosine, which may be an endogenous anticonvulsant, continues tn serve as a model but, for reasons such as poor brain distribution and an array of cardiovascular effects of agonists, has not yet yielded useful drugs. Elaboration of roles of receptor subtypes may give leads for drug design. 

ADP-ribosylation occurs on the GDP-liganded subunit, probably when it is in the trimeric state. With some toxin-mediated ADP-ribosylation reaaions, this may lead to effector activation by promoting exchange of GTP for the bound GDP (e.g., cholera toxin activation of adenylyl cyclase). In other cases, ADP-ribosylation prevents the reassociation of the trimeric G-protein with the receptor, thus negating the effect of agonist binding (e.g., the action of pertussis toxin). 

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