Local anesthetics structure

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

The low structural requirements for local anesthetic activity do not maintain in all classes of drugs. Structural requirements for biologic activity in fact follow a full continuum from those cases in which addition of a single carbon atom serves to abolish activity to the case of the local anesthetics that tolerate quite drastic alterations. 

The simplification of the local anesthetic phaimacophore of cocaine to an aryl substituted ester of ethanolamine has been described previously. Atropine (S2) is a structurally closely related natural product whose main biologic action depends on inhibition of the parasympathetic nervous system. Among its many other actions, the compound exerts useful spasmolytic effects. 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

Local anesthetics interact with peripheral nerve cell membranes and exert a pharmacological effect [34]. Potential oscillation was measured in the presence of 20 mM hydrochlorides of procaine, lidocaine, tetracaine, and dibucaine (structures shown in Fig. 16) [19]. Amplitude and the oscillatory and induction periods changed, the extent depending on the... 

FIG. 1 Molecular structures of the drugs examined in the delivery study the general anesthetics, alkanols (I), halothane (II), enflurane (III), isoflurane (IV), halogenated cyclobutane (V) the local anesthetics, dibucaine hydrochloride (VI), procaine hydrochloride (VII), tetracaine hydrochloride (VIII), lidocaine hydrochloride (IX), benzyl alcohol (X) the endocrine disruptor, bisphenol A (XI), and alkylbenzenes, benzene (XII), toluene (XIII), ethylbenzene (XIV), and propylbenzene (XV). 

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

Local anesthetics are positively charged amphiphiles in solution. We have selected hydrochlorides of dibucaine (DBC H ), procaine (PRC H ), tetracaine (TTC H ), and lido-caine (LDC H ). All of these drugs are structurally similar they consist of the substituted benzene ring and tertiary amine moieties, as shown by (VI)-(IX) in Fig. 1. The presence of the positive charge increases the solubility in water and in consequence, the anesthetic efficiency. 

Nonprescription topical anesthetics such as lidocaine and benzocaine are available in many types of products. Local anesthetics decrease discharges in superficial somatic nerves and cause numbness on the skin surface but do not penetrate deeper structures such as muscle where the pain often lies. 

The answer is local anesthetic properties it can block the initiation or conduction of a nerve impulse. It is biotransformed by plasma esterases to inactive products. In addition, cocaine blocks the reuptake of norepinephrine. This action produces CNS stimulant effects including euphoria, excitement, and restlessness Peripherally, cocaine produces sympathomimetic effects including tachycardia and vasoconstriction. Death from acute overdose can be from respiratory depression or cardiac failure Cocaine is an ester of benzoic acid and is closely related to the structure of atropine. 

Shimooka, T., Shibata, A. and Terada, H. (1992). The local anesthetic tetracaine destabilizes membrane structure by interaction with polar headgroups of phospholipids, Biochim. Biophys. Acta, 1104, 261-268. 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

Chemical structure of cocaine and synthetic local anesthetics. 

Characteristics of chemical structure. Local anesthetics possess a uniform structure. Generally they are secondary or tertiary amines. The nitrogen is linked through an intermediary chain to a lipophiUc moiety—most often an aromatic ring systenx... 

Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es-Ltillmann, Color Atlas of Pharmacology... 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

It is interesting that a nnmber of antihistamine, anticholinergic, and adrenergenic drngs having analogous chemical structures, also exhibit local anesthetic properties. It is possible that by interacting with internal axoplasmic membranes, they rednce the ion flow in particnlar, the flow of sodinm ions inside nerve cells. 

Encainide Encainide, 4-methoxy-N-[2-[2-(l-methyl-2-piperidinyl)ethyl]phenyl]-benza-mide (18.1.15), is synthesized by acylating 2-(l-methyl-2-piperidylethyl)aniline with 4-methoxybenzoic acid chloride. The chemical structure of encainide is substantially different than other local anesthetics and antiarrhythmics [25-27]. 

Benzonatate Benzonatate, p-butylaminobenzoate 2,5,8,11,14,17,20,23,26-nonaocta-cozan-28-ol (23.2.2), is synthesized by reesterifying the ethyl ester of 4-butylaminoben-zoic acid with the monomethyl ether nonaethylenglycol. It is a structural analog of the local anesthetic tetracaine [3,4],... 

All of the -blockers exert equilibrium-competitive antagonism of the actions of catecholamines and other adrenomimetics at -receptors. Probably the best-recognized action of these compounds that is not mediated by a p-receptor is depression of cellular membrane excitability. This effect has been described as a mem-brane-stabiUzing action, a quinidinelike effect, or a local anesthetic effect. This action is not too surprising in view of the structural similarities between p-blockers and local anesthetics. However, with the usual therapeu-... 

The basic components in the structure of local anesthetics are the lipophilic aromatic portion (a benzene ring), an intermediate chain, and the hydrophilic amine portion (Fig. 27.1). The intermediate chain has either an ester linkage from the combination of an aromatic acid and an amino alcohol or an amide linkage from the combination of an aromatic amine and an amino acid. The commonly used local anesthetics can be classified as esters or amides based on the structure of this intermediate chain. 

Model structure of local anesthetics showing aromatic portion, intermediate chain, and amine portion. 

Infiltration (i.e., the injection of local anesthetics under the skin) of the surgical site provides adequate anesthesia if contiguous structures are not stimulated. Since the onset of local anesthesia is rapid, the surgical procedures can proceed with little delay. Minimally effective concentrations should be used, especially in extensive procedures, to avoid toxicity from overdosage. 

---