Classical pharmacology

A scientific procedure that turns the classical pharmacology approach upside down. Instead of finding the elusive receptor for a known hormone or transmitter what classical pharmacology aims at, reverse pharmacology is initiated through the discovery of the receptor gene and aspires to the identification of the receptors unknown ligand. 

The findings of classical pharmacology serve as a basis for a discussion of dmg-receptor interactions at a biological level. To aid in this discussion, some classical pharmacological binding terms are briefly defined. The traditional dose-response curve is central to these discussions, and a representative example is given in figure 2.2. 

The preceding sections have explored classical pharmacological concepts based on the dose-response relationships in tissue or organ preparations. The enormous complexity of living systems and the remoteness of cause from effect (i.e., drug administration from pharmacological action) introduce many complications and artefacts into the study of such relationships. 

The binding and functional studies mentioned above do not provide any clear evidence for the putative existence of H3-receptor subtypes. Whereas it was probably the last receptor to be characterized through classical pharmacological methods, cloning of the H3-receptor gene is not yet achieved. Only this cloning is expected to provide us a direct conclusion about this important issue. 

In their last review about ergot alkaloids, Stoll and Hofmann (1) have given a short survey of the classic pharmacological and clinical activities of ergot derivatives. In the meantime some new, exciting results have been achieved which will be summarized here. 

Fig. 1.3 Pharmacokinetic/pharmacodynamic (PK/PD) modeling as combination of the classic pharmacological disciplines pharmacokinetics and pharmacodynamics (from [5]).

PURPOSE AND RATIONALE Surface anesthesia is used to anesthetize the cornea and conjunctiva of the eye and the mucous membranes in the mouth. The classical pharmacological test is the blockade of the rabbit corneal reflex as described by Regnier (1923) that has become a standard test method for evaluating local anesthetics (FuBganger and Schaumann 1931 Ther 1953a Quevauviller 1971 Muschaweck et al. 1986). These pharmacological methods are only partially suitable to determine the irritancy potential of local anesthetic on mucus membranes. Luduena et al. (1960) compared the mucus membrane irritancy of mepivacaine and lidocaine by the eye irritation method according to Hoppe (1950) and Draize et al. (1944). 

If a ligand had high affinity for a macromolecular target (as had been shown by classical pharmacological studies over many decades), it should be thermodynamically possible to measure the binding of the ligand to the receptor without... 

Examining the chemistry even more closely, we see that these 433 entities are derived from very few basic structures, or so-called chemical scaffolds upon which classical pharmacology works. After 120 years of conscious, and perhaps cautious, medicinal chemistry and pharmacology, we have come up with very few new chemical scaffolds to interact with the biological targets. 

ViRTUESAND PROBLEMS OF THE Classical Pharmacology Paradigmin Drug Discoveiy... 

Reverse pharmacology has great possibilities in drug discovery. Classical pharmacology starts with an active molecule and then looks for its effects and the receptor or enzyme through which these effects are exerted. For example, acetylcholine (ACh) was known from Loewy s experiments and from other studies in the periphery as an active substance. The target must be, by definition, an acetylcholine receptor. You knew it must exist you already had a name for it when you found it and all you had to do was find it, localize it, and discover its physicochemical, biochemical, and pharmacological characteristics. 

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