hydroxyls by chlorine atoms. However, DCI is also a partial βagonist, and therefore
cannot be used as a hypotensive drug. Propranolol (4.63) was the first major β-blocker
to be commercialized. Structure–activity studies using compounds such as DCI and
propranolol have led to the identification of some rules and regularities:
- The catechol ring system can be replaced by a great variety of other ring systems,
varying from phenylether (oxprenolol, (4.64)) and sulfonamides (sotalol (4.65)
to amides (labetalol, (4.66)), indoles (pindolol, (4.67); benzpindolol, (4.68)), and
naphthalene (propranolol, (4.63)). - The side chain is either the unchanged isopropylaminoethanol seen in isoproterenol or
an aryloxy-aminopropanol. The side-chain hydroxyl groups are essential to activity. - N-substituentsmust be bulky to ensure affinity to the β receptors; isopropyl is the
smallest effective substituent.
It is advantageous to have selective β 1 orβ 2 blockers, but this goal has been difficult to
achieve since most organs have both types of βreceptors in different proportions. While
β-blockers—primarily propranolol (4.63) and the mixed α–β-blocker labetalol (4.66)—
are antihypertensive agents, the β 1 activity of most of these compounds makes them
useful in the management of some forms of angina pectoris and in cardiac arrhythmia,
and they show promise in preventing second heart attacks. As mentioned, labetalol is a
phenylethanolamine derivative that is a competitive inhibitor of β 1 ,β 2 , and α 1 adrener-
gic receptors. It is more potent as a βantagonist than an αantagonist. Labetolol has
two stereogenic carbon atoms and thus exists as a mixture of four stereoisomers; this
NEUROTRANSMITTERS AND THEIR RECEPTORS 235