Antitussive drugs

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. 

TRPVl is involved in the cough reflex [155] and 5-iodo-RTX was shown to function as a potent antitussive drug in guinea pigs [156]. 

Antitussive drugs, 3 (1963) 89 Anti-ulcer drugs, of plant origin, 28 (1991) 201... 

Codeine is similar to morphine in terms of properties, but its pain-relieving ability is significantly less and it causes addiction to some degree. This drug is very effective in oral use and is used for average to moderate pain. It is often used as an antitussive drug. Synonyms for codeine are codyl, acutus, and others. 

The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It appears likely that both central and peripheral effects play a role. 

Codeine is the methylic ether of morphine (3-methylmorphine) and can be isolated from opium during the extraction of morphine, but is usually prepared by the methylation of morphine. Codeine is used in medicine as an antitussive drug and furthermore it has analgesic properties. It may cause addiction, but less than morphine. 

Fig. 3.1 Morphine 1 has been the lead structure for the development of the major analgesic fentanyl 2, the antitussive drug dextromethorphan 3, the constipating drug loperamide 4, and the neuroleptic drug haloperidol 5.

Dextromethorphan hydrobromide is an antitussive drug with no analgesic or addictive action. Its antitussive effect is similar to codeine. The recommended oral dose for adults is 10-30mg three to six times a day, not to exceed 120mg daily. It is absorbed rapidly and completely when taken orally with a lag time of 15-30 min [72]. 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

The closely related compound 55 is an orally active antitussive drug. 

Figure 2.15) show very different receptor subtype selectivities. Compound 53 has a more than 300-fold higher affinity for the 5-HT3 ion channel than for the G-protein-coupled 5-HT4 receptor (K 5-HT3 = 3.7 nM vs. Kt 5-HT4 > 1000 nM), whereas compound 54 binds almost exclusively to the 5-HT4 receptor (ff 5-HT3 >10 000 nM vs. K 5-HT4 =13.7 nM selectivity > 700) [28,29], The chemically related compound DF-1012, 55 (Figure 2.15), is an orally active antitussive drug [30],... 

TRK-851 is a clinical candidate for an antitussive drug it has a novel, complex morphinan ring system. The development of TRK-851 was motivated by the finding that NTI, a selective 8 opioid receptor antagonist, showed antitussive effect. In this section we will describe the process of developing TRK-851, including the structure-activity relationship (SAR) studies on NTI derivatives and the difficulties encountered in overcoming a defect in the metabolism of a prototype clinical candidate, TRK-850. 

These observations strongly supported the feasibility of 5 opioid receptor antagonists as antitussive drugs that did not have p opioid receptor-mediated side effects. 

Among opioids, morphinans (Fig. 1) play an important role as therapeutically valuable drugs. Representative examples of the morphinan class of compounds (Fig. 2) are p-opioid analgesic agents for the treatment of moderate-to-severe pain such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogs (e.g. levorphanol, butorphanol) [19-21], Codeine is also an effective antitussive drug. The oxymorphone derivatives naloxone [22] and naltrexone [23] represent... 

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