more drugs from the four starter groups listed above with one or more drugs from the
following four groups:
- Central α 2 agonists (e.g., clonidine)
- Alpha-blockers (e.g., prazosine)
- Vasodilators (e.g., dihydralazine, minoxidil)
- Depletors of neurotransmitter biogenic amine stores (e.g., reserpine)
When selecting an agent, hypertensive complications and/or concomitant co-morbidities
must be considered. For instance, when hypertension is being treated in the presence of
angina pectoris, a β-blocker or Ca^2 +channel antagonist is preferable to a diuretic; when
hypertension is being treated in the presence of prostatic hyperplasia (with associated
impairment of urination),α-blockers are preferred. For uncomplicated mild hyper-
tension, monotherapy is preferable to polytherapy. When polytherapy is being used,
drugs that rationally complement each other—by acting through different mechanistic
pathways—should be employed. For example, the combination of an ACE-inhibitor
with a diuretic (thiazide) is a potent and rational combination. Combining two ACE
inhibitors would not be a rational combination; nor would combining a β-blocker with
verapamil, since both produce bradycardia(decreased heart rate) as a side effect.
Whether pursuing monotherapy or polytherapy, non-pharmacological measures, such
as weight reduction or the use of a low Na+diet, are useful adjuncts.
5.24 PEPTIDE AND STEROID HORMONES AS STARTING
POINTS IN DRUG DESIGN
As has been demonstrated in this chapter, hormones are superb starting points in the
design and discovery of new chemical entities as potential therapeutics. Hormones are
molecular messengers that have the capacity to influence a variety of metabolic and
chemical processes throughout the organism. Consequently, the design of agonists or
antagonists to a particular hormonal receptor imparts a capacity for selective modifica-
tion of hormonal function. Moreover, being small molecules, the majority of hormones
can be readily “analoged” and explored as putative drugs.
Although steroids have been studied for many years, steroid hormones continue to be
a rich area of medicinal chemistry study. Steroids continue to be evaluated for their
therapeutic role in the treatment of cancer, especially malignancies whose growth char-
acteristics are hormonally responsive. In recent years, the increased recognition of the
role of steroids in the brain has resulted in ongoing projects to evaluate steroids as gen-
eral anasthetics and anticonvulsants. Also, the search for compounds that bind to steroid
receptors, but which are not steroidal in their molecular structure, is another important
area of research.
Likewise, peptide hormones are also an area of continuing drug design research. The
plethora of peptide hormones both within the brain and external to the brain continues to
grow in complexity. Accordingly, peptidic hormones mediate a diversity of metabolic
processes and are logical targets for a variety of pathological states. The geometries and
conformations of short peptides can be comprehensively studied using molecular mechan-
ics force field calculations in conjunction with molecular dynamics or Monte Carlo
HORMONES AND THEIR RECEPTORS 381