Antagonists potency

There are two practical reasons to err toward the correction of the ICso of an antagonist to estimate the Kb- The first is that an overestimation of antagonist potency will only result in a readjustment of values upon rigorous measurement of antagonism in subsequent analysis. However, more importantly, if the correction is not applied then there is a risk of not detecting weak but still useful antagonism due to an underestimation of potency (due to nonapplication of the correction factor). These reasons support the application of the correction in all cases as a default. 

Kenakin, T. P., and Beek, D. (1981). The measurement of antagonist potency and the importance of selective inhibition of agonist uptake processes. J. Pharmacol. Exp. Ther. 219 112-120. 

Mutations specific for reduced antagonist potency H251L (6.52) (bovine) V84L (3.32) K152A (EL2) W243A (6.48)... 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

It is not surprising that a DA antagonist (especially those acting primarily on Di receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with Dj antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12 months and can persist indefinitely in some cases. 

Figure 17.8 Comparison of the antagonist potencies of some neuroleptics on different NT receptors. Data are shown for haloperidol (HAL), chlorpromazine (CPZ), clozapine (CLOZ) and risperidone (RISP) acting on dopamine Dj and D2, 5-HT2 (S2), alpha (0(2) adrenoceptors and cholinergic muscarinic receptors (M). The height of each column shows an average of the dissociation constants obtained from a number of publications (see Seeman 1990). The values, which can vary some fiftyfold, are expressed as the negative logarithms (i.e. 9 = 10 M,lnM) so that the higher the column, the more potent the compound. The order of potency of the four compounds at each receptor is shown alongside...

Table 2 Antagonist Potencies and Opioid Receptor Affinities of TIPP Analogues... 

In 1995 the dipeptide H-Dmt-Tic-OH was reported to be a 6-opioid antagonist with unprecedented 6-receptor affinity (K = 0.022 nM) and 6 receptor selectivity (Kf/Kf = 150,000) [47]. However, in a direct comparison under identical assay conditions, this compound showed about 30 times lower 6-antagonist potency and 6 times lower 6-receptor selectivity... 

These compounds have very prolonged (minutes to hours) In vitro and In vivo antagonist activities. In some cases (compounds 6 and 37) It was not possible to obtain even an estimate of the In vitro antagonist potencies (pA2)> In other cases (compounds 34,35) the estimates are lower limits and represent only estimates since due to the prolonged activity, true equilibrium measurement cannot be made. 

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