Potency, interpretations

Null method, physiological or pharmacological effects are translations of biochemical events by the cell. The null method assumes that equal responses emanate from equal initial stimulation of the receptor therefore, when comparing equal responses, the complex translation is cancelled and statements about the receptor activity of agonists can be made. Relative potencies of agonists producing equal responses thus are interpreted to be measures of the relative receptor stimuli produced by the agonists at the receptor see Chapter 5.6.2. 

Some Chemical Considerations Relevant to the Mouse Bioassay. Net toxicity, determined by mouse bioassay, has served as a traditional measure of toxin quantity and, despite the development of HPLC and other detection methods for the saxi-toxins, continues to be used. In this assay, as in most others, the molar specific potencies of the various saxitoxins differ, thus, net toxicity of a toxin sample with an undefined mixture of the saxitoxins can provide only a rough approximation of the net molar concentration. Still, to the extent that limits can be placed on variation in toxin composition, the mouse assay can in principle provide useful data on trends in net toxin concentration. However, the somewhat protean chemistry of the saxitoxins makes it difficult to define conditions under which the composition of a mixture of toxins will remain constant thus, attaining a reproducible level of mouse bioassay toxicity is difficult. It is therefore useful to review briefly some of the chemical factors that should be considered when employing the mouse bioassay for the saxitoxins or when interpreting results. Similar concepts will apply to other assays. 

All fire smoke is toxic. In the past two decades, a sizable research effort has resulted in the development of over twenty methods to measure the toxic potency of those fire smokes (6). Some methods have been based on determinations of specific chemical species alone. Values for the effect (e.g., lethality) of these chemicals on humans are obtained from (a) extrapolation from preexisting, lower concentration human exposure data or from (b) interpretation of autopsy data from accident and suicide victims. The uncertainty in these methods is large since ... 

These and many other questions are best answered when one has in hand a series of compounds that differ not only in potency but also in qualitative effect. Only in this way can statistical, theoretical, and modem quantitative and qualitative analytic methods be applied to offer the most meaningful interpretation of the results and to appreciate fully the subtle relationships between molecular structure and biologic effect. Indeed, in this case, we need these compounds to define what is even meant by biologic effect. ... 

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

Interpretation of results for the A -methylated aralkylguanidines (Table 3.29) is less clear, as there appear to be marked species differences. Monoamine oxidase in rat tissues 387] is more sensitive to inhibition by compounds of this type than that in cat or guinea-pig tissues [389], and the increase in potency found on -chloro substitution is less marked in other species than it is in rats. For any single aryl group A -methylation or A A"-dimethylation may either slightly increase or decrease activity. 

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. 

This example emphasizes the need for data upon the intraventricular potency of narcotic analgesics whereby transport factors would largely be eliminated and it is to be hoped that procedures for the direct administration of drugs to the brain (technically difficult and often unreliable in their present state [281]) will be improved in the near future. Alternatively, the development of a meaningful isolated tissue assay for analgesia would do much to improve our interpretation of structure-activity relationships in this field (see page 262). 

An alternative way to validate the critical function eliciting the disease-relevant phenotype is the use of tool modulators these can be small molecules, peptides, or antibodies that may not have the properties to be considered a drug, but may display sufficient potency and selectivity to be used to interrogate the specific protein function in the relevant system. Such tools, however, are rarely available with the required characteristics to allow for a robust interpretation of the experiment. The exception is represented by the... 

Reducing the dimensionality of the descriptor space not only facilitates model building with molecular descriptors but also makes data visualization and identification of key variables in various models possible. Notice that while a low dimension mathematically simplifies a problem such as model development or data visualization, it is usually more difficult to correlate trends directly with physical descriptors, and hence the data become less interpretable, after the dimension transformation. Trends directly linked with physical descriptors provide simple guidance for molecular modifications during potency/property optimizations. 

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