The Selectivity of Drugs

1. 1 What is Selectivity? purpose, and crop protective agent for the A biologically-active substance is said to be second, but there is no fundamental difference selective if it strongly affects certain cells with­ of principle in their mode of action. out causing any change in others, even when the Drug therapy has two, fundamentally two kinds of cells are close neighbours. In living opposed divisions. The first of these strives to organisms, there are many substances, often improve the action of one of the cell's natural quite small molecules, which have been chosen agents by modifying the molecule in order to for their specificity. This choice has been made localize or intensify its action. For instance, under the strong pressure of natural selection, the solubility can be decreased to make it form unhurried by any consideration of time. Such a deposit, or a change is made so that it becomes chemical compounds operate the metabolism a poorer fit on the naturally-occurring destruc­ of the cells and tissues, and ensure their health, tive enzyme. Both of these devices have proved survival, and reproduction. Important among useful in therapy, e. g. with steroid hormones. the smaller of these selective molecules are Such drugs, which seek to improve on Nature vitamins, coenzymes, hormones, neurotrans­ by performing more desirably, are called mitters, inorganic ions, nutritional fragments, agonists.

1 Introduction.- 1.1 What is Selectivity?.- 1.2 The aims and accomplishments of Selectivity.- References.- 2 Three principles that control selectivity.- 3 Steps in the correlation of structure with biological activity.- 3.1 Introduction.- 3.2 The first correlations.- 3.3 The concept of ‘receptors’.- 3.4 The receptor as an enzyme or permease.- 3.5 The receptor as a nucleic acid.- 3.6 The receptor as a coenzyme, or other small molecule.- 3.7 Other aspects of receptors.- 3.8 Targets that are not necessarily receptors.- 3.9 Regression analysis.- 3.10 Conclusion.- References.- 4 Favourable differences in distribution: the first principle of selectivity.- 4.1 Some examples.- 4.2 Qualitative aspects of distribution.- 4.3 Quantitative aspects of distribution.- 4.4 The permeability of natural membranes.- 4.5 Metabolic change leading to activation.- 4.6 Metabolic change leading to inactivation.- 4.7 Synergism and antagonism.- 4.8 Conclusion.- References.- 5 Favourable differences in biochemistry: the second principle of selectivity.- 5.1 Introduction.- 5.2 Analogous enzymes.- 5.3 More analogous enzymes: the dihydrofolate reductases.- 5.4 Absence of enzymes from one of the species I. The sulphonamides and organophosphates.- 5.5 Absence of enzymes. II Further examples.- 5.6 Metabolite analogues (mostly antagonists).- 5.7 Other utilizable biochemical differences.- 5.8 Conclusion.- References.- 6 Favourable differences in cell structure: the third principle of selectivity.- References.- 7 Acquired resistance to drugs: the loss of selectivity.