mixture is used clinically. The different stereoisomers have varying activities as α
andβ antagonists. All of the β-antagonist properties reside in the (1R,1'R)-isomer;
α 1 -antagonist properties are in the remaining three isomers, with the (1S,1'R)-isomer
having the greatest activity. Clinically, labetolol has some advantages in the manage-
ment of hypertension since the α-receptor blockade produces hypotensive vasodilation,
while the β-blockade component prevents the reflex tachycardia that may be associated
with the vasodilation. Unfortunately, at the pharmacokinetic level, labetolol is hindered
by an extensive first-pass effect.
Because adrenergic agents such as β-blockers find such extensive use as hypotensive
drugs, the etiology and drug combination treatment of hypertension are of considerable
interest. A discussion in any detail of this complex and confusing field goes beyond the
scope of this book, however. Other aspects of hypertension will be discussed in con-
nection with the renin and vasopressin systems and calcium channel blockers.
Clinically, there now exists an abundance of β-blocker congeners. Propranolol was
the first β-blocker to be introduced into therapy, in 1965. Now, four decades later, more
than 20 different analogs have been marketed in different countries: alprenolol, bupra-
nolol, pindolol, oxprenolol, talinolol, sotalol, timolol, metoprolol, metipranol, atenolol,
bunitrolol, acebutolol, nadolol, carazolol, penbutolol, mepindolol, carteolol, befunolol,
betaxolol, celiprolol, bisoprolol, bopindolol, esmolol, carvedilol, and tertatolol. (Of these
compounds, acebutolol, atenolol, betaxol, bisoprolol, esmolol, and metoprolol are β 1 selec-
tive agents.) This avalanche-like increase in commercially available β-sympatholytics
is driven by market forces rather than by medicinal chemistry. Variation of the basic
molecular structure will often create a new patentable chemical entity, but not neces-
sarily a drug with a novel or improved action.
4.3.7 The Clinical–Molecular Interface: Depression
as an Adrenergic DisorderDepression is one of the most common disorders of mood (affective disorders). It is
characterized by a specific alteration in mood (sadness, apathy), a negative self-concept
(self-reproach, self-blame), regressive and self-punitive wishes (desire to hide or die),
vegetative changes (insomnia, anorexia, loss of libido), and change in activity level
(agitation or listlessness). Traditionally, depression was classified as either reactive or
endogenous. A reactive depression was a response to a psychosocial precipitating factor,
such as death of a spouse; an endogenous depression occurred in the absence of a pre-
cipitating factor and arose from a biological predisposition. Depressions have also been
categorized as bipolarorunipolar. A bipolar depression (manic-depressive illness)
236 MEDICINAL CHEMISTRY