Propargylamines.The propargylamines are Kcatinhibitors or suicide substrates of
MAO, forming covalent derivatives with the flavine group of the enzyme. Pargyline
(8.39), while an MAOI, is used as a hypotensive agent, even though it is incompatible
with certain foods and sympathomimetic drugs (i.e., adrenergic agonists). It may act by
negative feedback on norepinephrine synthesis, and has a long duration of action.
Carbolines.Harmine (8.40) and related carboline alkaloids are reversible MAO-A
inhibitors, but are not used therapeutically. Deprenyl (8.41) is a selective MAO-B
inhibitor and produces an increase in DA levels, but does not influence NE or 5-HT
concentrations. It has been proposed as an antidepressant in aging males.
8.2.7 Emerging Enzyme Targets: Caspases and KinasesAs evidenced by the ongoing discussion in this chapter, enzymes have historically rep-
resented very important targets in drug design. This trend will undoubtedly continue.
Although many enzymes continue to be targeted for purposes of drug design, two
families of enzymes are emerging as important sources for future drug design: kinases
and caspases. Both of these enzyme families trigger cascades of molecular events that
exert profound effects on cellular functioning; both regulate crucial biological
processes. Both families are therefore strong candidates for drug design. However, there
are some major hurdles that must be confronted. Since there are many different kinases
and many different caspases, the drug design process must strive for selectivity, devel-
oping a compound that inhibits one particular kinase (or caspase) without necessarily
inhibiting the entire family. Furthermore, since both of these enzymes are integral to
fundamental biochemical processes, care must be taken to ensure that the enzyme
inhibitors are not excessively toxic.
8.2.7.1 Kinases
For regulating crucial biological processes, living organisms depend upon a family of
enzymes called protein kinases. Although they were first recognized in the 1950s, it is
only recently that their potential in drug discovery has been more fully exploited.
Current estimates suggest that there are several thousand kinase enzymes. They work
by attaching phosphate groups to other proteins, thereby activating cellular processes,
including transcription of new proteins. Protein phosphorylation is recognized as the
most important factor in the regulation of protein function by switching cellular activi-
ties from one state to another, thereby regulating gene expression, cell proliferation, and
cell differentiation. All kinases have “on” switches and “off ” switches that keep them
under tight control. Protein kinase A, for example, uses a regulatory subunit—a second
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