Local anesthetics activity

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). 

Zipeprol [34758-83-3] (58) is another European antitussive with a wide range of pharmacological effects, including antispasmodic, antihistaminic, and local anesthetic activities (85,86). It has been reported that zipeprol has been abused in Italy because high doses cause hallucinations (87). Spontaneous withdrawal symptoms similar to those of opiates have been observed withdrawal symptoms can also be precipitated by naloxone. Zipeprol can be... 

The finding that the benzoyl ester, tropacocaine (14), possessed local anesthetic activity showed that the carbomethoxy group was not required for activity. 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

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. 

Risocaine (28) manages to retain local anesthetic activity even without having a "basic ester" moiety.10 Its synthesis follows classic lines involving esterification of p-nitrobenzoic acid with thionyl chloride followed by reaction with propanol, and then catalytic reduction to complete the scheme. 

Perivine 25 exhibits an enhanced local anesthetic activity with respect to cocaine in the rabbit-comea test (230). Tabersonine (67) shows 25% of the hypotensive activity of reserpine on cats, ( )-vincadifformine shows 50% activity, whereas (—)-vincadifformine (ent-10) is inactive (231). 

Local anesthetic activity is also shown by uncharged substances, suggesting a binding site in apolar regions of the channel protein or the surrounding lipid membrane. 

Cocaine (8), from Erythroxylum coca Lam., besides causing euphoria by inhibiting the dopamine transport protein (DAT) responsible for its recreational and illegal use, exerts a local anesthetic activity through blocking sodium channels and is still used as a probe for this target. 

Pharmacology Flecainide has local anesthetic activity and belongs to the membrane stabilizing (Class I) group of antiarrhythmic agents it has electrophysiologic effects... 

B. Anticholinergic agents, such as procainamide and disopyramide, are relatively contraindicated in patients with glaucoma. Procainamide is hypotensive rather than hypertensive. The local anesthetic activity of procainamide would have no adverse interaction with the diabetes mellitus. 

Mechanism of Action An antiarrhythmicthat prevents sodium current across myocardial cell membranes. Has potent local anesthetic activity and membrane stabilizing effects. Slows AV and His-Purkinje conduction and decreases action potential duration and effective refractory period. Therapeutic Effect Suppresses ventricular arrhythmias. 

Similarly, reaction of 2-dimethylaminomethylene-3-oxoalkanoates or 2-di-methylaminomethylene-1,3-cyclohexanediones with 2-phenyl-5(4/7)-oxazolone 146, generated in situ from hippuric acid, affords 6-substituted 3-(benzoyl-amino)-2-oxo-2//-pyran-5-carboxylates 204 and 3-(benzoylamino)-7,8-dihydro-2//-l-benzopyran-2,5(6//)-diones 206, respectively. These compounds showed strong local anesthetic activity (Scheme 7.62). ... 

Nadolol is noteworthy for its very long duration of action its spectrum of action is similar to that of timolol. Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye. Levobunolol (nonselective) and betaxolol (E -selective) are also used for topical ophthalmic application in glaucoma the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective 13-receptor antagonist. 

Lidocaine (synonyme lignocaine) was introduced as the first amide in 1944 and is the most commonly used LA today. It has a rapid onset of action with intermediate duration and an intermediate toxicity. The maximum tolerated dose with infiltration or injection is 200 mg (500 mg when combined with adrenaline). Lidocaine is dealkylated in the liver to monoethylglycine xylidide and glycine xylidide which retain local anesthetic activity. It is available in a variety of preparations including creams, gels, patches and solutions, often in combination with adrenaline. 

Courtney, K. R., Strichartz, G. R. Structural elements which determine local anesthetic activity, in Local Anesthetics. Handbook of Experimental Pharmacology 1987, 81, edited by G. R. Strichartz, 53-94, Springer Verlag, Berlin. 

Local anesthetic activity is usually demonstrated by compounds which possess both an aromatic and an amine moiety separated by a lipophilic hydrocarbon chain and a polar group. In the clinically useful agents (Table 2) the polar group is an ester or an amide. Activity may be maintained, however, when the polar function is an etlier, lliiuelher, ketone, or tliioester. 

In rejecting claims 1-8 of Albrecht s application, the examiner noted that certain mono-basic esters of carbazole were reported to have powerful local anesthetic activity, whereas the corresponding dibenzofuran compounds were less effective. The further disclosure of the bis-basic dibenzofuran as having some minimal anesthetic activity was sufficient, the examiner alleged, to motivate a PHOSITA to make the bis-basic esters of the carbazole compounds like those claimed in Albrecht s application, since the prediction would be that the bis-basic ester of the carbazole would be a more effective anesthetic than the disclosed bis-basic dibenzofuran. It would, therefore, be obvious to make these compounds, and the claims should be rejected. 

N-Substituted amides, derivatives of saturated N-heterocycles, antiarith-mic and local-anesthetic activities of 91UK852. 

There have been no recent studies on the pharmacology of samandarine alkaloids. Samandarine is a potent local anesthetic 48). Cardiac depressant effects (48,49) and inhibition of binding of a radiolabeled batracho-toxin analog to sodium channels (50) are consonant with the potent local anesthetic activity of samandarine. Samandarine alkaloids show antimicrobial activity (51 and references therein). 

Similar to timolol, levobunolol is a noncardioselective P-blocker without significant local anesthetic activity or ISA. 

Like timolol and levobimolol, metipranolol is a noncardioselective p-blocker without significant local anesthetic activity or ISA. Metipranolol has been used worldwide, both orally in the treatment of systemic hypertension and topically for the treatment of elevated lOP. 

Bupivacaine exhibits stereoselectivity of local anesthetic activity, CNS and cardiac toxicity and pharmacokinetics. /J-Bupivacaine is more potent, more toxic and more rapidly cleared than its 5-isomer. 

Bucricaine (centbucridine) is a quinolone derivative with local anesthetic activity. 

Zabka M, Vitkova Z, Burelova A, Mandak M. Formulation and local anesthetic activity of carbizocaine in collyria. Cesk Farm 1988 37(10) 457 60. 

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