terminated by cellular re-uptake, mediated through a high-affinity transporter system.
There are two glycine receptors: the strychnine-sensitive Cl−channel glycine receptor,
and the strychnine-insensitive glycine subsite on the NMDA receptor complex.
The first receptor is the strychnine-sensitive Cl−channel glycine receptor. The plant
alkaloid strychnine (4.204) is an antagonist for this receptor, binding with nanomolar
affinity. The glycine receptor, like other members of the family, is formed by a pen-
tameric arrangement surrounding a central ion pore; there is significant homology with
the GABAAreceptor. This receptor exists as a macromolecular complex composed of
two homologous polypeptides:α(48 kDa) and β(58 kDa). Binding sites for glycine and
strychnine are found in the subunit. Mutations of the αsubunit, particularly a leucine
for arginine substitution at position 271, lead to a very rare neurological disorder termed
hyperekplexia. Patients with this disease demonstrate an exaggerated startle response to
environmental stimuli, jumping dramatically or even collapsing in response to minor
situational stimuli such as a car door shutting. The strychnine-sensitive Cl−channel
glycine receptor functions as an anion channel. Permitting chloride anion to enter neu-
rons causes neuronal hyperpolarization (increased negative charge within the cell),
which in turn decreases neuronal excitability. Therefore, this glycine receptor is
inhibitory and, when binding to this receptor, glycine is acting as an inhibitory neuro-
transmitter. Autoradiography studies with [^3 H]strychnine show that these receptors are
clustered mainly in the spinal cord and brainstem.
The strychnine-insensitive glycine subsite on the NMDA receptor complex is the
other major glycine receptor. On this receptor, unlike the strychnine-sensitive receptor,
glycine is linked to neuronal excitation. Glycine is a necessary cofactor for the func-
tioning of the excitatory NMDA receptor; when binding to this receptor, glycine is
acting as an excitatory neuromodulator.
Both the strychnine-sensitive and insensitive receptors are involved in pathological
processes and thus are targets for drug design. The strychnine-sensitive site may be a
useful target when designing drugs (as agonists) to treat spasticity. Spasticity is a symp-
tom arising from damage to the spinal cord or to the descending corticospinal tract from
the brain that is characterized by increased tone, sometimes painful, in the muscles of
the arms and legs. The strychnine-insensitive receptor may be a useful target when
designing drugs (as antagonists) to treat either epilepsy or stroke.
In medicinal chemistry, the strychnine-insensitive receptor has received more
attention. For example, the 5-nitro derivative of 6,7-dichloroquinoxalinedione has been
identified as a highly potent antagonist of the glycine subsite on the NMDA receptor.
282 MEDICINAL CHEMISTRY