2.11.4.1 Targets 1–3
The first three categories target endogenous messengers. An endogenous messenger is a
molecule synthesized in one or more cells or organs within the body and transported to
other cells or organs within the body, enabling the transmission of information and
effecting an alteration in biochemical function in the receiving cell or organ. In a
systems-centered approach to drug design, the human body is regarded as a collection
of physiological systems; the role of the three control systems (nervous, endocrine,
immune) is to maintain homeostasis (i.e., a balanced and regulated internal
electrical/chemical/cellular milieu). As a simplified generalization, the nervous system
controls short-term homeostasis via electrical biochemical processes (using neurotrans-
mitters), the endocrine system controls intermediate-term homeostasis via chemical bio-
chemical processes (using hormones), and the immune system controls long-term
homeostasis via cellular biochemical processes (using immunomodulators). (Keep in
mind that there is actually significant overlap between the nervous and endocrine sys-
tems, the endocrine and immune systems, and even the nervous and immune systems.)
Nevertheless, messenger molecules are ideal candidates around which to design thera-
peutic molecules, since they permit the drug designer to have molecular-level access to
the body’s own endogenous control systems.
Many human disease states arise directly from abnormalities of messenger mole-
cules. The symptoms of Parkinson’s disease arise from an underactivity of the
dopamine neurotransmitter, whilst psychosis arises from overactivity of the dopamine
neurotransmitter. The symptoms of Alzheimer’s disease involve underactivity of the
acetylcholine neurotransmitter, and the symptoms of Huntington’s disease involve
defective metabolism of the GABA neurotransmitter. At the hormonal level, diabetes
results from either an absolute or a functional deficiency of the insulin hormone,
whereas hypothyroidism is produced by a deficiency of thyroid hormone. Although the
mechanistic relationship is somewhat less direct, many other human pathological con-
ditions involve abnormalities in homeostasis (e.g., systemic arterial hypertension [high
blood pressure], cardiac arrhythmias [chest palpitations], bronchospasm [asthma],
abnormal gastric secretions [peptic ulcer disease], altered gastric motility [irritable
bowel syndrome], abnormal bladder contractions [spastic bladder]) and thus can be
treated via appropriate “tweaking” of one or more of the three control systems. Finally,
some diseases produce end-organ pathology that in turn affects homeostatic processes.
A stroke, for example, may enhance the activity of glutamate, which then produces
excitotoxicity by binding to ligand-gated ion channels (thus augmenting and enlarging
the neuropathology of the stroke). Once again, such pathological states may be treated,
in theory and in practice, by altering the control systems.
Messenger targets are ideal for drug design. Most neurotransmitters, many hormones,
and a number of immunomodulators are small molecules of low molecular weight. By
designing and synthesizing analogs of these molecules, it is possible to produce agonists
and antagonists that enable therapeutic modulation over endogenous control systems.
2.11.4.2 Targets 4–6
The next three categories are nonmessenger targets. Not all pathological processes
can be treated by adjustments of endogenous control systems; therefore, nonmessenger
RECEPTORS: STRUCTURE AND PROPERTIES 99