Agents blocking

A wide variety of compounds possess anticholinergic activity. The development of such compounds has been largely empiric and based principally on atropine us the prototype. 

Nevertheless, structural permutations have resulted in compounds that do not have obvious relationships to the parenl molecule. The following clussincation delineates the major chemical types encountered  

Anticholinergic compounds may he considered chemieah that have some similarity to ACh but contain additionalsuh-stitueitts that enhance their binding to the cholinergic receptor. 

Etaminalion of the active compounds discussed in the following sections reveals that at least one cyclic substituent iplienyl. thienyl, or other) is a common feature in almost all anticholinergic molecules. Aromatic substitution is often g l in connection with the acidic moiety of the ester func- on. Virtually all acids used, however, are of the aryl-substi-tnied acetic acid variety. Use of aromatic acids leads to low mivity of these compounds as anticholinergics but potential itivity as local anesthetics. 

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C14H30CI2N2O4. White powder prepared from dimethylaminoethanol and succinyl chloride, followed by methylation. Neuromuscular blocking agent used to relax skeletal muscles during certain types of surgical operation. 

RNHCH.CH(OHlCH— R R P Adrenergic receptor blocking agents 473... 

RNHCH CH(OHiCH - heteroarvl H /3-Adrenergic receptor blocking agents 179... 

With aldehydes, primary alcohols readily form acetals, RCH(OR )2. Acetone also forms acetals (often called ketals), (CH2)2C(OR)2, in an exothermic reaction, but the equiUbrium concentration is small at ambient temperature. However, the methyl acetal of acetone, 2,2-dimethoxypropane [77-76-9] was once made commercially by reaction with methanol at low temperature for use as a gasoline additive (5). Isopropenyl methyl ether [116-11-OJ, useful as a hydroxyl blocking agent in urethane and epoxy polymer chemistry (6), is obtained in good yield by thermal pyrolysis of 2,2-dimethoxypropane. With other primary, secondary, and tertiary alcohols, the equiUbrium is progressively less favorable to the formation of ketals, in that order. However, acetals of acetone with other primary and secondary alcohols, and of other ketones, can be made from 2,2-dimethoxypropane by transacetalation procedures (7,8). Because they hydroly2e extensively, ketals of primary and especially secondary alcohols are effective water scavengers. 

Malonates can also be used as blocking agents in the formulation of one-part urethanes. These systems, curable by moisture, are used, for example, for automotive windshield gla2ing (53) (see Urethane polymers). 

One-part urethane sealants (Table 3) are more compHcated to formulate on account of an undesirable side reaction between the prepolymer s isocyanate end and water vapor which generates carbon dioxide. If this occurs, the sealant may develop voids or bubbles. One way to avoid this reaction is to block the isocyanate end with phenol and use a diketamine to initiate cure. Once exposed to moisture, the diketamine forms a diamine and a ketone. The diamine reacts with the isocyanate end on the prepolymer, creating a cross-link (10). Other blocking agents, such as ethyl malonate, are also used (11). Catalysts commonly used in urethane formulations are tin carboxylates and bismuth salts. Mercury salt catalysts were popular in early formulations, but have been replaced by tin and bismuth compounds. 

Propafenone. Propafenone hydrochloride, an arylketone, is stmcturaHy similar to the P-adrenoceptor blocking agents. It has been in use in the former West Germany since 1977 and was introduced in the United States in 1990. Its effects may result from a combination of weak calcium channel blocking, weak nonselective -adrenoceptor blocking, and sodium channel blocking activity. Propafenone is effective in treating supraventricular tachyarrhythmias, ventricular ectopic beats, and ventricular arrhythmias. It is the most frequendy prescribed medication for ventricular arrhythmias in Europe (32). 

Class II Antiarrhythmic Agents The p-Adrenoceptor Blocking Agents... 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Other P"Adrenoceptor Blocking Agents. Several other p-adrenoceptor blocking agents are in development as antiarrhythmic agents. These include carteolol, flestolol, and bopindolol (see Table 1). 

The electrophysiological effects of amiodarone may be a composite of several properties. In addition to prolonging action potential duration and refractory period in ad tissues of the heart, the compound is an effective sodium channel blocker (49), calcium channel blocker (50), and a weak noncompetitive -adrenoceptor blocking agent (51). Amiodarone slows the sinus rate, markedly prolongs the QT interval, and slightly prolongs the QRS duration (1,2). 

Metoprolol. Metoprolol tartrate (Table 1), also a Class II antiarrhythmic agent, is a HpophiHc, cardioselective P -adrenoceptor blocking agent... 

Nadolol. Nadolol (Table 3) is a hydrophilic, nonselective -adrenoceptor blocking agent having no ISA and no membrane-stabilizing activity. It is useful for the treatment of hypertension and chronic stable exertional angina (98,99,108). 

Other P"Adrenoceptor Blocking Agents. Carteolol hydrochloride (Table 1) is also a Class II antiarrhythmic agent. In three separate studies in patients having angina pectoris, carteolol was considered effective as evidenced by a reduction in the frequency and severity of anginal episodes, reduction in the amount of nitroglycerin consumed, improvement of ECG parameters, or an increase in the duration of trea dmill exercise (42). 

Qf-receptor blocking agent, 1, 176 Phenylalanine hydroxylase in tyrosine synthesis from phenylalanine, 1, 261 L-Phenylalanine hydroxylase mechanism, 1, 261 Phenyl azide formation... 

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