Cocaine-derived local anesthetics

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

Many substances of widely different chemical structure abolish the excitability of nerve fibers on local application in concentrations that do not cause permanent injury and that may not affect other tissues. Sensory nerve fibers are most susceptible, so that these agents produce a selective sensory paralysis, which is utilized especially to suppress the pain of surgical operation. This property was first discovered in cocaine, but because of its toxicity and addiction liability, it has been largely displaced by synthetic chemicals. The oldest of these, procaine (novocaine), is still the most widely used. Its relatively low toxicity renders it especially useful for injections, but it is not readily absorbed from intact mucous membranes and is therefore not very effective for them. Many of its chemical derivatives are also used. They differ in penetration, toxicity, irritation, and local injury as well as in duration of action and potency. Absolute potency is not so important for practical use as is its balance with the other qualities. If cocaine is absorbed in sufficient quantity, it produces complex systemic actions, involving stimulation and paralysis of various parts of the CNS. These are mainly of toxicological and scientific interest. Its continued use leads to the formation of a habit, resembling morphinism. This is not the case with the other local anesthetics. 

While cocaine is still used for ear, nose, and throat surgery, Lidocaine, a synthetic derivative of cocaine, is the most widely used local anesthetic. 

Because of cocaine s toxicity and addictive properties, a search began for synthetic substitutes for cocaine. In 1905, procaine was synthesized and became the prototypic local anesthetic for half a century. Newer derivatives include mepivacaine and tetracaine (Figure 13.1). Briefly, the SAR of local anesthetics revolves around their hydrophobicity. Association of the drug at hydrophobic sites, such as the sodium channel, is believed to prevent the generation and conductance of a nerve impulse by interfering with sodium permeability (i.e., elevating the threshold for electrical excitability). 

Most of the local anesthetic agents in current medical use are of the.se types (Tables 20-2 and 20-. ). The benzoic acid derivatives are esters that were developed from cocaine, while the aniline derivatives are amides developed ftom iso-gramine. Both types of derivative have chemical structutes that normally have the general format ... 

Extension of Tropine Alkaloids. Here again, medicinal chemists have gone beyond nature by molecular modification. While cocaine possesses topical anesthetic activity but no local infiltration value as an anesthetic, a number of very useful, local anesthetic agents such as procaine and lidocaine have been derived from our knowledge of the structure of cocaine. Chemists have broadened the scope of usefulness of the cocaine structure. 

Matschulan (65) has also found that, when acedicon, a thebaine derivative, is injected subcutaneously into guinea pigs in doses of 0.01-0.3 g./kg., the local anesthetic effect of cocaine on the skin is prolonged considerably. 

Eucaine, the first unnatural analog of cocaine to be synthesized, was reported in 1918. As shown by the bold lines in its structure, eucaine is very similar to cocaine. Eucaine was found to function as a local anesthetic, and it did not produce mydriasis, nor was it addictive however, it was not the "Holy Grail of local anesthetics because it was highly toxic. Another analog of cocaine is piperocaine, which, as shown by the boldfaced lines, retains some of the basic elements of cocaine but is structurally more different from cocaine than is eucaine. Piperocaine has the same beneficial characteristics as eucaine but is only one-third as toxic as cocaine. A further iteration of the structure is seen in the form of procaine, which is commonly known as Novocain, perhaps the most successful anesthetic agent derived from cocaine. Novocain is about one-fourth as toxic as cocaine and is not habit-forming. 

---