Antitussive activity

Modifications of the morphine skeleton have produced butorphanol [42408-82-2] (35) and drotebanol [3176-03-2] (36), which in animal models have demonstrated antitussive activity much greater than that of codeine (51,52). Butorphanol is also a potent analgetic of the narcotic antagonist type (51). Both compounds possess a unique 14-hydroxyl group. 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

The synthesis (60) and potent antitussive activity (61) of dimemorfan [36309-01-0] (41), D-3-methyl-/V-methylmorphinan, have been reported. This compound, prepared by a modification of the Grewe process, differs from dextromethorphan only by having a methyl group, rather than a methoxy group, in the 3 position. 

Noscapine [128-62-1] (45) is the second most abundant alkaloid found in opium. Unlike most opium alkaloids, however, it has an isoquinoline rather than a phenanthrene ting system. Noscapine was first isolated in 1817 but its antitussive activity was not demonstrated pharmacologically until 1952 (63). Clinical studies have confirmed its effectiveness. It is not a narcotic and has a wide margin of safety when given orally. Death could be produced in rats only with doses > 800 mg/kg (64). Noscapine is isolated from the water-insoluble residue remaining after processing opium for the manufacture of morphine. 

Chlophedianol [791-35-5] (49) is the most potent antitussive ia a series of compounds originally synthesi2ed as potential antispasmodics. It is about one-third as active as codeiae and has weak antispasmodic and local anesthetic activity. Although the onset of antitussive activity is slow, the duration is prolonged. Chlophedianol can be prepared from 2-chlorophenylphenyLmethanone (67). 

Diphenhydramine [58-73-1] (55) was originally developed as an antihistamine and was first used clinically for this purpose in 1946 (see HiSTAMlNE AND HISTAMINE antagonists). In addition to this primary effect, however, central antitussive activity has also been demonstrated in animals (75,76) and in humans (77). Its antitussive activity is about half that of codeine. Drowsiness is the most frequent side effect. Diphenhydramine can be prepared as follows (78) ... 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

Fominoben [18053-31 -1] (66) is another nonnarcotic drug which has shown antitussive activity comparable to codeiae when adrninistered both orally or parenteraHy ia a variety of animal species (95). 

Although chemically related to the above cycloalkylamines, pentethylcyclanone (71) is stated to have antitussive activity. The compound is prepared rather simply by alkylation of the anion (70a) of the self-condensation product of cyclopentanone (70) with N-(2-chloroethyl)-morpholine. ... 

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

In fact, esters of amino alcohols and 2,2-disubstituted plii iiylacetic acids show useful antitussive activity the mecha-lM iii of action may include bronchiodilation. Double alkylation III the anion of phenylacetonitrile with 1,4-dibromobutane gives llit i cyclopentane-substituted derivative (33). Saponification... 

An effect of opening K+ channels is to hypetpolarise the primary sensory neurons. Similarly to local anaesthetics, this makes the cell less likely to produce an action potential because more depolarising stimuli are needed to overcome the block. NS 1619 is an example of this type of drug which has initially shown antitussive activity in a variety of experimental systems. 

Quaternary ammonium salts such as carcainium chloride (RSD 931) have been shown to be antitussive whilst having much reduced local anaesthetic activity. Whilst the molecular mechanisms underlying this antitussive activity is not understood, RSD 931 appears to be A8 fibre selective and may represent a novel class of antitussive drug. More recently JMF2-1 a lidocaine derivative that blocks Na+ channels has had beneficial effects in the airways without significant local anaesthetic activity. 

Oxymorphone is approximately 10 times more active than morphine. Euphoric effects as well as vomiting are expressed significantly stronger than in morphine. Oxymorphone also displays poor antitussive activity. 

Oxymorphone is 10 times as potent as morphine, with actions similar to those of hydromorphone. Oxymorphone, however, has httle antitussive activity, and as such is a useful analgesic in patients with pulmonary disease who need to retain the ability to cough. 

Amino-2,3-dihydrobenzofurans such as (501) and (502) are useful as antidepressants and hypotensives (70USP3513239). Substituted 5-acyl-2,3-dihydrobenzofuran-2-carboxylic acids of the type (503) possess diuretic and antitussive activities (69GEP1927393). Derivatives of the 3-phenyl-2 (3H)-benzofuranone type (504) exhibit musculotropic and anaesthetic effects. Amethone (505) is used against bronchial asthma and also shows antihistaminic activity (47JA980). 

Dimethoxanate [477-93-0] (47) and pipazethate [2167-85-3] (48) are related phenothiazine derivatives that have shown antitussive activity. Unlike many phenothiazines, these do not produce central nervous system depression or analgesia at therapeutic doses. They are both somewhat less potent than codeine. It has been suggested that the unique side chain that is similar to, but shorter than, the one on benzonatate, may be at least pardy responsible for the antitussive effects. Both dimethoxanate and pipazethate are the result of molecular modifications of classical phenothiazines, such as promethazine [60-87-7], which possess antitussive activity in addition to central nervous system depressant activity. Dimethoxanate can be prepared by the reaction of phenothiazine- 10-carboxylic acid chloride with p-dimethylaminoethoxyethanol (66). 

Among the long list of diverse structures reported to possess central antitussive activity is Ahtetrahydrocannabinol (THC) [1972-08-3] (68), the principal psychoactive component of marijuana (see PSYCHOPHARMACOLOGICALAGENTS). This compound was found to be comparable to codeine against electrically induced cough in the anesthetized cat (90). Two other naturally occurring cannabinoids, cannabidiol and cannabinol, are inactive. 

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