brain structures. The macroscopic features of these alterations include fibrous gliosis
(i.e., “brain scarring”) with cellular shrinkage and atrophy. At the biochemical level,
various theories of epileptogenesis have been put forth, including the mossy fibre
sprouting hypothesisand the dormant basket cell hypothesis. The mossy fibre sprout-
ing hypothesis postulates an upregulation of excitatory coupling between neurons medi-
ated by N-methy-D-aspartate [NMDA] glutamatergic receptors, which are activated in
chronic epileptic brain under circumstances that would not lead to activation in normal
brain. In contrast, the dormant basket cell hypothesis suggests a downregulation of
inhibitory coupling between neurons such that the connections which normally drive
γ-aminobutyric acid [GABA] releasing inhibitory interneurons are disturbed, thereby
rendering them functionally dormant.
Although such glutamatergic and GABAergic processes are obvious participants in
the molecular mechanism of epileptogenesis, there are other molecular claimants to the
throne. For example, in the kindling animal model of epileptogenesis (in which repetitive,
subconvulsive, electrical stimulation evokes progressively prolonged electrographic/
behavioral responses that culminate in generalized seizures), neurotrophic peptides,
such as nerve growth factor [NGF], play a facilitative role in neuronal synaptic reorga-
nization, thereby contributing to the evolution of the epileptogenic state. Clearly, the
future development of antiepileptogenic agents must exploit the full range of targets,
extending from amino acid neurotransmitters to peptidic neuromodulators.
Although well exemplified by ion channel active agents, the problem of “sympto-
matic” versus “curative” druggable targets in drug design is by no means restricted to
these classes of compounds. The treatment of Alzheimer’s dementia with cholinesterase
enzyme inhibitors, rather than with agents such as anti-amyloid compounds, is an analo-
gous example of symptomatic drugs being developed in preference to “disease stabilizing”
or curative drugs.
7.5 Targeting Cell Membrane Proteins: Ligand-Gated Ion Channels
Voltage-gated ion channels are transmembrane proteins that change their conformation
in response to changes in the transmembrane electrical potential gradient. Ligand-gated
ion channels, on the other hand, are transmembrane proteins that change their confor-
mation in response to binding to a particular ligand. Ligand-gated ion channel proteins
are also sometimes called ionotropic receptors, because once the receptor is occupied
by the ligand the resulting change in protein conformation opens a channel that enables
ions to flow through. The term ionotropic receptor distinguishes these proteins from
metabotropic receptors, in which the binding of the ligand to the receptor exerts the
biological effect via G proteins.
There are two main families of ligand-gated ion channel proteins that act as ionotropic
receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor,
the glycine receptor, and a class of serotonin receptor. The other family comprises various
types of ionotropic glutamate receptors. Since these various ligand gated ion channels
are activated by neurotransmitters, the medicinal chemistry of these proteins is presented
in detail in chapter 4.
432 MEDICINAL CHEMISTRY