Synthetic anesthetics

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Dozens of compounds have been used in in vivo fluonne NMR and MRI studies, chosen more for their commercial availability and established biochemistry than for ease of fluonne signal detection [244] Among the more common of these are halothane and other fluormated anesthetics [245, 246], fluorodeoxyglucose [242 243], and perfluormated synthetic blood substitutes, such as Fluosol [246], a mixture of perfluorotnpropylamine and perfluorodecahn Results have been Imut-ed by chemical shift effects (multiple signals spread over a wide spectral range) and long acquisition times... 

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. 

Continued synthetic work in the general area of anesthetic null lies revealed the interesting fact that the amide function can III reversed. That is, compounds were at least equally effective 111 which the amide nitrogen was attached to the aromatic ring iiiiil the carbonyl group was part of the side chain. 

With very few exceptions, the biological activities of synthetic steroids tend to parallel those of the naturally occurring hormones on which they are patterned. Compounds with distant pharmacological activity are, as a rule, quite rare. It is thus intriguing that inclusion of a tertiary amine at the 11 position of a pregnane leads to a compound with activity far removed from its close analogues. The agent in question, minaxalone (47), exhibits anesthetic activity. 

Uses. n-Pentane has found use as an anesthetic an expl suppressant when mixed with a halogen-ated hydrocarbon and included in aircraft fuel (Ref 13) a jet engine fuel (Ref 16a) as a base for synthetic rubbers and plastics a parent compd for the formation of nitropentanes and azido nitro pentanes used as expls and propints (Refs 15a, 15b 21a) also, as a parent compd for fluorine-contg resin binders which impart both thermal stability and, in conjunction with metal hydrides, high impulse to solid propints (Ref 15b)... 

Classical or conventional pharmaceutical agents in combination with lactide/glycolide polymers have been widely studied since about 1973. In general, these compounds are bioactive agents usually produced by synthetic chemistry, with molecular weights of less than a few hundred and relatively stable structures. Examples include steroid hormones, antibiotics, narcotic antagonists, anticancer agents, and anesthetics. 

Cocaine is still a drug of choice among many physicians as a topical local anesthetic because the drug has vasoconstrictive qualities (shrinks and stops the flow of blood). Synthetic local anesthetics such as novacaine and xylocaine (lidocaine) have also been discovered and used extensively as a local anesthetic. 

Early synthetic work on the conversion of kojic acid into 3-hydroxy-4-pyridinones was instigated in the hope of finding potential anesthetics (25), but the results of this search proved disappointing. However, various investigators over the subsequent seven and a half decades have found a range of specialized applications and potential uses for several hydroxypyridinones, a few of which are mentioned later. 

Chemical structure of cocaine and synthetic local anesthetics. 

Uses Coolant and refrigerant herbicide and fumigant organic synthesis-methylating agent manufacturing of silicone polymers, pharmaceuticals, tetramethyl lead, synthetic rubber, methyl cellulose, agricultural chemicals and nonflammable films preparation of methylene chloride, carbon tetrachloride, chloroform low temperature solvent and extractant catalytic carrier for butyl rubber polymerization topical anesthetic fluid for thermometric and thermostatic equipment. 

Hydralazine is a vasodilating drug and inhibition of DNA methyltransferases in the range of 10-20 pM have been reported in vitro [83]. In addition, hypomethylation in cell culture has also been shovm [84]. Also the local anesthetic procaine [85] and its amide analog procainamide [84] have been identified as DNA methyltransferase inhibitors. Synthetic analogs of procaine have shown activity only around 500 pM [86] (Figure 8.10). 

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. 

Fentanyl is a semi-synthetic opioid, ft is a much more powerful version of morphine. Fentanyl is used during surgery as an anesthetic and is extremely dangerous when taken in a nonmedical context. First created in Belgium in the 1950s, fentanyl is 80 times more powerful than morphine. Due to its strength, fentanyl is listed as a Schedule I narcotic in the United States. 

Historically, local anesthetics have been known for many years. Cocaine, the first such agent, was isolated in 1860 and introduced for clinical application in 1884. Procaine was developed as a synthetic analog of cocaine in 1905 and lidocaine was synthesized in 1943. The development of new chemical entities as putative local anesthetics remains an ongoing activity in medicinal chemistry. 

The synthesis of optically active diaryl methanols 27 is of particular synthetic value, since their core structure represents a molecular scaffold which is relevant to numerous biologically active compounds and pharmaceuticals possessing an-tihistaminic, anticholinergic, local-anesthetic, and laxative properties. Examples include neobenodine 28, orphenadrine 29, and carbinoxamine 30 [31]. 

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