Structureactivity Relationships

¡-Blockers are among the most widely employed antihyper-tensives and are also considered the first-line treatment for glaucoma. Most of ¡-blockers are in the chemical class of aryloxypropanolamines. The first ¡-blocker, dichloroisopro-terenol (DCI), was reported in 1958 by Powell and Slater.58 DCI differs structurally from ISO in that the agonist directing 3'4'-di-OH groups have been replaced by two chloro groups. This simple structural modification, involving the replacement of the aromatic OH groups, has provided the basis for nearly all of the approaches used in subsequent efforts to design and synthesize therapeutically useful ¡-blockers.35 Unfortunately, DCI is not a pure antagonist but a partial agonist. The substantial direct sympathomimetic action of DCI precluded its development as a clinically useful drug.

Pronethalol was the next important ¡-blocker developed. Although it had much less intrinsic sympathomimetic activity (ISA) than DCI, it was withdrawn from clinical testing because of reports that it caused thymic tumors in mice. Within 2 years of this report, however, Black and Stephenson59 described the ¡-blocking actions of propranolol, a close structural relative of pronethalol. Propranolol has become one of the most thoroughly studied and widely used drugs in the therapeutic armamentarium. It is the standard against which all other ¡-blockers are compared.

Propranolol belongs to the group of ¡-blockers known as aryloxypropanolamines. This term reflects the fact that an —OCH2— group has been incorporated into the molecule between the aromatic ring and the ethylamino side chain. Because this structural feature is frequently found in ¡-blockers, the assumption is made that the —OCH2— group is responsible for the antagonistic properties of the molecules. However, this is not true; in fact,

Serine Palmitoyltransferase

the —OCH2— group is present in several compounds that are potent jS-agonists.60 This latter fact again leads to the conclusion that it is the nature of the aromatic ring and its substituents that is the primary determinant of jS-antago-nistic activity. The aryl group also affects the absorption, excretion, and metabolism of the jS-blockers.61 Note that the side chain has been moved from C2' to the CT position from the naphthyl ring.

The nature of the aromatic ring is also a determinant in their ^-selectivity. One common structural feature of many cardioselective jS-blockers is the presence of a para-substituent of sufficient size on the aromatic ring along with the absence of meta-substituents. Practolol is the prototypical example of a ^-blocker of this structural type. It was the first cardioselective ^-blocker to be used extensively in humans. Because it produced several toxic effects, however, it is no longer in general use in most countries.

Like jS-agonists, jS-directing tert-butyl and isopropyl groups, are normally found on the amino function of the aryl-oxypropanolamine jS-blockers. It must be a secondary amine for optimal activity.

For arylethanolamine adrenergic agonists, the j-OH-substituted carbon must be in the R absolute configuration for maximal direct activity. However, for jS-blockers, the S-OH-substituted carbon must be in the S absolute configuration for maximal jS-blocking activity. Because of the insertion of an oxygen atom in the side chain of the aryl-oxypropanolamines, the Cahn-Ingold Prelog priority of the substituents around the asymmetric carbon differs from the agonists. This is effect of the nomenclature rules. The pharmacologically more active enantiomer of S-blockers interacts with the receptor recognition site in same manner as that of the agonists. In spite of the fact that nearly all of the S-blocking activity resides in one enantiomer, propranolol and most other jS-blockers are used clinically as racemic mixtures. The only exceptions are levobunolol, timolol, and penbutolol, with which the (S) enantiomer is used.

Propranolol (log P = 3.10) is the most lipophilic drug among the available S-blockers, and thus it enters the CNS much better than the less lipophilic drug such as atenolol (log P = 0.10) or nadolol (log P = 1.29). The use of lipophilic jS-blockers such as propranolol has been associated with more CNS side effects, such as dizziness, confusion, or depression. These side effects can be avoided, however, with the use of hydrophilic drugs, such as atenolol or nadolol. The more lipophilic drugs are primarily cleared by the liver, and so their doses need to be adjusted in patients with liver disease. In contrast, the less lipophilic drugs are cleared by the kidney and so their doses need to be adjusted in patients with impaired renal function.


Propranolol (Inderal, others) is the prototypical and nonselective jS-blocker. It blocks the j1- and jS2-receptors with equal affinity, lacks ISA, and does not block a-receptors. Propranolol, like the other j-blockers discussed, is a competitive blocker whose receptor-blocking actions can be reversed with sufficient concentrations of jS-agonists. Currently, propranolol is approved for use in the United States for hypertension, cardiac arrhythmias, angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, migraine prophylaxis, and essential tremor. In addition, because of its high lipophilicity (log P = 3.10) and thus its ability to penetrate the CNS, propranolol has found use in treating anxiety and is under investigation for the treatment of a variety of other conditions, including schizophrenia, alcohol withdrawal syndrome, and aggressive behavior.

Some of the most prominent effects of propranolol are on the cardiovascular system. By blocking the j-receptors of the heart, propranolol slows the heart, reduces the force of contraction, and reduces cardiac output. Because of reflex sympathetic activity and blockade of vascular j2-receptors, administration may result in increased peripheral resistance. The antihypertensive action, at least in part, may be attributed to its ability to reduce cardiac output, as well as to its suppression of renin release from the kidney. Because it exhibits no selectivity for ^-receptors, it is con-traindicated in the presence of conditions such as asthma and bronchitis.

A facet of the pharmacological action of propranolol is its so-called membrane-stabilizing activity. This is a nonspecific effect (i.e., not mediated by a specific receptor), which

Propranolol And Membrane

is also referred to as a local anesthetic effect. Both enan-tiomers possess membrane-stabilizing activity. Because the concentrations required to produce this effect far exceed those obtained with normal therapeutic doses of propranolol and related jS-blockers, it is unlikely that the nonspecific membrane-stabilizing activity plays significant role in the clinical efficacy of j-blockers.

Propranolol is well absorbed after oral administration, but it undergoes extensive first-pass metabolism before it reaches the systemic circulation. Lower doses are extracted more efficiently than higher doses, indicating that the extraction process may become saturated at higher doses. In addition, the active enantiomer is cleared more slowly than the inactive enantiomer.62

One of the major metabolites after a single oral dose is naphthoxylactic acid. It is formed by a series of metabolic reactions involving N-dealkylation, deamination, and oxidation of the resultant aldehyde. Another metabolite of particular interest is 4-hydroxypropranolol, which is a potent S-blocker that has some ISA. It is not known what contribution, if any, 4-hydroxypropranolol makes to the pharmacological effects seen after administration of propranolol. The half-life of propranolol after a single oral dose is 3 to 4 hours, which increases to 4 to 6 hours after long-term therapy.

Other Nonselective p-Blockers. Several other clinically used nonselective j-blockers include nadolol (Corgard), pindolol (Visken), penbutolol (Levatol), car-teolol (Cartrol, Ocupress), timolol (Blocadren, Timoptic), levobunolol (Betagan), sotalol (Betapace), and metipra-nolol (OptiPranolol). Structures of these compounds are shown in Figure 16.15. The first five of these blockers are used to treat hypertension. Nadolol is also used in the long-term management of angina pectoris, whereas timolol finds use in the prophylaxis of migraine headaches and in the therapy following myocardial infarction. Sotalol is used as an antiarrhythmic in treating ventricular arrhythmias and atrial fibrillation because in addition to its jS-adrenergic blocking activity, this agent blocks the inward K+ current that delays cardiac repolarization.

Carteolol, timolol, levobunolol, and metipranolol are used topically to treat open-angle glaucoma. These agents lower intraocular pressure with virtually no effect on pupil size or accommodation. They thus offer an advantage over many of the other drugs used in the treatment of glaucoma. Although the precise mechanism whereby ^-blockers lower intraocular pressure is not known with certainty, it is believed that they may reduce the production of aqueous humor. Even though these agents are administered into the eye, systemic absorption can occur, producing such adverse effects as bradycardia and acute bronchospasm in patients with bronchospastic disease.

Pindolol possesses modest membrane-stabilizing activity and significant intrinsic jS-agonistic activity. Penbutolol and carteolol also have partial agonistic activity but not to the degree that pindolol does. The jS-blockers with partial agonistic activity cause less slowing of the resting heart rate than do agents without this capability. The partial agonistic activity may be beneficial in patients who are likely to exhibit severe bradycardia or who have little cardiac reserve.

Timolol, pindolol, penbutolol, and carteolol have half-life values in the same range as propranolol. Nadolol undergoes very little hepatic metabolism and most of this drug is excreted unchanged in the urine. As a result, the half-life of nadolol is about 20 hours, making it one of the longest-acting jS-blockers. Timolol undergoes first-pass metabolism but not to the same extent that propranolol does. Timolol and penbu-tolol are metabolized extensively such that little or no unchanged drug excreted in the urine. Pindolol is metabolized by the liver to the extent of 60%, with the remaining 40% being excreted in the urine unchanged.

Si-selective blockers (second generation)

The discovery that jS-blockers are useful in the treatment of cardiovascular disease, such as hypertension, stimulated a search for cardioselective jS-blockers. Cardioselective


Carteolol: antihypertensive & antiglaucoma h3c h3c ch3

ococh3 Metipranolol: antiglaucoma



Levobunolol, S(-) isomer of bunolol antiglaucoma o ^ ' ^nhc(ch3)3


Nadolol: antihypertensive

Penbutolol: antihypertensive oh



oh nhc(ch3)3


Sotalol: antiarrhythmias &

only phenylethylamine

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