Potency differences

Interpretations of activity differences between a pair of agonists in terms of events at the receptor usually rest upon the assumption that drug transport factors play only a secondary role. Although this might seem reasonable in the case of a- and /3-prodine in view of their isomeric nature, preliminary results indicate that their potency differences may be related primarily to differences in their ease of penetration of the C.N.S. (in rats brain levels of /3-prodine exceed those of the a-isomer) [280]. If these findings be substantiated, conformational differences may then be related chiefly to processes governing the transport and distribution of the diastereoisomeric pair rather than to drug-receptor associations. 

In the absence of distribution data (and knowledge of preferred conformation — at least in the axial phenyl examples), the significance of potency differences amongst the isomeric esters (LXXXIll-LXXXV) cannot, however, be judged. Of the more rigid reduced acridine congeners (LXXXVI), only the e-phenyl isomer has been obtained and this lacks hot-plate activity in mice [286]. 

Several lines of evidence suggest that tt2A- and a2c-receptors operate also in wild-type mice as integral parts of the presynaptic feedback loop. Experiments on peripheral tissues, e.g. heart atria, demonstrated that the a2c-subtype mediates autoinhibition by low concentrations of noradrenaline in wild-type mice, whereas the potency of noradrenaline at the a2A-subtype was lower (Fig. 4) (Hein et al. 1999). This potency difference of noradrenaline for the a2-receptors correlated with the affinity difference of noradrenaline for the tt2A- and a2c-subtypes, respectively. Furthermore, there is no evidence so far that the expression of the remaining o(2-receptor subtypes was altered in mice carrying deletions in a2A- or a2c-receptor genes (Link et al. 1995 Altman et al. 1999). 

In particular, we would emphasize the need to obtain full dose-response curves and a careful assessment of potency differences and efficacy differences based on these full dose-response relationships. This is critical If one Is to develop Insight Into those features of structure and conformation which are critical to receptor recognition and those which are critical to transduction (, ). Such Insight Is essential In the development of antagonists, superagonists, etc. 

Pharmacokinetics plays a very important role in the manner in which opioids are abused. Morphine and many of its derivatives are slowly and erratically absorbed after oral administration, which makes this route suitable for long-term management of pain but not for producing euphoria. In addition, opioids undergo considerable first-pass metabolism, which accounts for their low potency after oral administration. Heroin is more potent than morphine, although its effects arise primarily from metabolism to morphine. The potency difference is attributed to heroin s greater membrane permeability and resultant increased absorption into the brain. 

Several of these relative potencies differ from those given in Hannigan et al. (1998) see Table 10.25. 

EXTENSIONS AND COMMENTARY In a comparison between the 2-carbon compound (2C-G-3) and the 3-carbon compound (G-3) the vote goes towards the phenethylamine (the 2-carbon compound). With the first member of thi s series (2C-G versus GANESHA) this was a stand-off, both as to quantitative effects (potency) and qualitative effects (nature of activity). Here, with the somewhat bulkier group 1 ocated at the definitive 3,4-positions, the nod is to the shorter chain, forthe first time ever. The potency differences are small, and maybe the amphetamine is still a bit more potent. But there are hints of discomfort with this latter compound that seem to be absent with the phenethylamine. The more highly substituted compounds (q.v.) more clearly define these differences. 

For each compound, the lowest tested dose able to elicit emesis in any of the animals tested at that dose was recorded as the minimum effective dose. The minimum effective emetic dose thus was an observed value, not a statistically derived value. For potency comparisons, minimum effective dose values serve to show the existence of large potency differences. 

Figure 4.3 Example of an activity cliff illustrated by closely related adenosine deaminase inhibitors having dramatic potency differences. The introduction of a hydroxyl group that coordinates a zinc cation in the active site of the enzyme adds several orders of magnitude to the potency of an inhibitor.

A different example is provided by a set of elastase inhibitors. These ligands are also related by continuous SARs. This is reflected by the presence of highly potent inhibitors with diverse structures and, in addition, structurally similar ligands that display only minor potency differences. However, in contrast to factor Xa, 3D analysis reveals a more complex picture. Specifically, elastase accepts multiple binding modes, each of which is adopted by structurally... 

Figure 4.6 Ribonuclease inhibitors, a) Analogs of different nucleotides adopt distinct binding modes, b) Closely related analogs that differ only in the position of two phosphate groups and bind in very similar conformations show significant potency differences.

SARI is constituted by two individual score components that evaluate the similarity spectrum within a compound class and potency differences between related ligands as the major determinants of SAR characteristics. Two-dimensional structural similarity of compounds is calculated using the Tanimoto coefficient for MACCS structural keys and potency is represented by either pA or pICso values. Both individual scores of the SARI are first calculated in a raw numerical form and then transformed into final normalized scores. 

The similarity threshold for ligand pairs that are considered in calculating the discontinuity score is set to 0.6. This relatively soft threshold value ensures that also potency differences between remotely similar compounds are taken into account and thus enables a thorough assessment of putative activity cliffs, which is further emphasized by multiplication by pair-wise ligand similarity. 

Figure 4.7 Potency difference versus 2D similarity of enz5rme inhibitors. Each data point represents a pair-wise comparison of inhibitors within an activity class. Data points are grayscale-coded according to potency represented as the sum of their pA i values using a continuous spectrum from light grey (lowest combined potency) to black (highest combined potency). Distributions are shown for four sets of enz5me inhibitors that represent different types of SARs, as discussed in the text (a) factor Xa, (h) ribonuclease A, (c) thromboxane S5mthase and d) carbonic anhydrase.

The anticoagulant activity of warfarin is a classic example of stereoselective drug action. 5-warfarin in vivo is from two- to five-fold more anticoagulant than its i -enantiomer. This potency difference is coincidentally offset by the two-or five-fold greater plasma clearance of the distomer. 

The adverse effects of local anesthetics are well established (3,4). The safety advantages claimed for newer agents have to be treated with much reserve. With increasing experience, discovery of optimal doses, and understanding of potency differences, the tolerability of... 

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