Structurally specific drugs

A number of compoimds that possess remarkable pharmacological actions are essentially the structurally specific drugs. Though the physical characteristics of the drug play an important role in the biological activity, yet the chemical properties do exert their justified influence on the activity. 

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Simple mathematical calculations by the first pharmacologists in the 1930s indicated that structurally specific drugs exert their action in very small doses and do not act on all molecules of the body but only on certain ones, those that constitute the drug receptors. For example, Clark [407] calculated that ouabain applied to the cells of the heart ventricle, isolated from the toad, would cover only 2.5% of the cellular surface. These observations prompted Clark [407,408] to apply the mathematical approaches used in enzyme kinetics to the effects of chemicals on tissues, and this formed the basis of the occupancy theory for drug-receptor interaction. Thus, pharmacological receptor models preceded accurate knowledge of receptors by many years. 

Although the related alkaloid brucine (and possibly also vomicine [867, 868]) would appear to exhibit activity which is qualitatively identical [869] but quantitatively less potent [870], strychnine (LIII, Fig. 4) [871] can be regarded as a structurally specific drug on account of its specific action on the post-synaptic inhibitory mechanisms in the spinal cord [754, 872-881]. Indeed, so specific is this activity that the recent demonstrations [882-885] that strychnine appears to block only some of the post-synaptic inhibitory mechanisms in the cerebral cortex are open to the interpretation [882, 886-890] that the mechanisms unaffected by the drug in this location utilise a different transmitter from the transmitter involved in the spinal cord. 

The lack of structural specificity among sedative-hypnotic drugs has been alluded to before. It is perhaps not too surprising that quinazolones, too, show this activity. The prototype, methaqualone (149), is obtained in a single step from the condensation of the"anthranilamide, 148, with o-toluidine.(The reaction may well involve first formation of the bisamide cycli-zation will then give the quinazolone ring system.) Condensation... 

Gschwend DA, Sirawaraporn W, Santi DV, Kuntz ID. Specificity in structure-based drug design identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Proteins Struct Funct Genet 1997 29 59-67. 

Unlike mass transport across membranes, which relates to chemical structure in predictable ways, the potencies of drugs as seen in pharmacological, pharmacodynamic, or other tests are highly structurally specific within a class of drugs and are without commonality across classes. A drug s activity involves a complex merging of these separate structural influences, with bioavailability always one of the concerns. Such concern is minimal when a truly superficial effect is involved, however. For example, the most potent antiseptic as measured in the test tube is likely to have... 

JPF Bai, GL Amidon. Structural specificity of mucosal-cell transport and metabolism of peptide drugs. J Pharm Sci 9 969-978, 1992. 

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