Partial agonists examples

The development of new drugs usually requires the synthesis of large numbers of structurally related compounds. If a set of agonists of this kind is tested on a particular tissue, the compounds are often found to fall into two categories. Some can elicit a maximal tissue response and are described as full agonists in that experimental situation. Others cannot elicit this maximal response, no matter how high their concentration, and are termed partial agonists. Examples include ... 

Recently, two examples of the separation of enantiomers using CCC have been published (Fig. 1-2). The complete enantiomeric separation of commercial d,l-kynurenine (2) with bovine serum albumin (BSA) as a chiral selector in an aqueous-aqueous polymer phase system was achieved within 3.5 h [128]. Moreover, the chiral resolution of 100 mg of an estrogen receptor partial agonist (7-DMO, 3) was performed using a sulfated (3-cyclodextrin [129, 130], while previous attempts with unsubstituted cyclodextrin were not successful [124]. The same authors described the partial resolution of a glucose-6-phosphatase inhibitor (4) with a Whelk-0 derivative as chiral selector (5) [129]. 

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. 

An example of the application of this method to the measurement of the affinity of the histamine receptor partial agonist E-2-P (with full agonist histamine) is shown in Figure 5.19. A full example of the application of this method for the measurement of partial agonists is given in Section 12.2.2. 

The situation is different with a partial agonist (see Section 1.4.1). Inactivation of any of the receptors by, for example, dibenamine or phenoxybenzamine will now reduce the maximal response to the partial agonist, without the initial parallel shift in the log concentration-response curve that would be seen (e.g., Figure 1.24) with a full agonist if the tissue has a substantial receptor reserve. 

Some antagonists combine the ability to block open ion channels with a competitive action at or near the agonist binding site. A well-characterized example is the nicotinic blocker tubocurarine (see Chapter 6). Agonists may also be open channel blockers, thus limiting the maximal response that they can elicit. Such agents (e g., decamethonium) may therefore behave as partial agonists when tested on an intact tissue ... 

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