402, Dr. Lu
Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., pp. 277-282.
1. Johnson, G. and Bigge, C.F., Recent Advances in Excitatory Amino Acid Research, Annual Reports in Medicinal Chemistry, 26, 11-22 (1991).
2. Monn, J.A., and Schoepp, D.D., Recent Progress in Excitatory Amino Acid Research, Annual Reports in Medicinal Chemistry, 29, 53-64 (1994).
3. Cosford, N.D.P., McDonald, I.A., Schweiger, E.J., Recent Progress in Antiepileptic Drug Research, Annual Report in Medicinal Chemistry, 33, 61-70 (1998).
4. Cooper, J.R., Bloom, F.E., Roth, R.H., The Biochemical Basis of Neuropharmacology, 7th ed., pp.171-190 (1996).
Skinner, K.J., The Chemistry of Learning and Memory, A Special Report in Chemical & Engineering NEWS, October 7, 1991.
Leeson, P.D., Iversen, L.L., The Glycine Site on the NMDA Receptor:
Structure-Activity Relationships and Therapeutic Potential, J.
Med. Chem., 37, 4053-4067 (1994).
Johansen, T.N., Frydenvang, K., Ebert, B., Krosgaard-Larsen, P., Madsen,
U., Synthesis and Structure-Activity Studies on Acidic Amino Acids and Related
Diacids as NMDA Ligands, J. Med. Chem.,
37, 3252-3262 (1994).
Educational Objectives and Study Guidelines
A student should be able to:
1. Explain the possible role(s) of excitatory amino acid neurotransmitter receptors in learning or in causing certain neurological disorders.
2. Explain how NMDA antagonists or glycine receptor antagonists may be used as anticonvulsants and/or as neuroprotectants.
3. Identify the structural differences between EAA receptor agonists and antagonists and predict their therapeutic potential.
4. Explain how positive and negative allosteric effectors work.
Handout # 2
Excitatory Amino Acid Receptors
Like GABA, the amino acid L-glutamate is one of the most important
neurotransmitters in the mammalian CNS. Almost
all CNS neurons can be excited by L-glutamate through a variety of different
receptors known as excitatory amino acid (EAA) receptors. These receptors can be further divided into two main classes
known as the ionotropic receptors and the metabotropic receptors.
Amongst the ionotropic receptors, NMDA and AMPA receptors are the most
widely studied. Both NMDA and AMPA
receptor subtypes are involved in learning and can also mediate neuronal
degeneration and even cell death. For
this reason, extensive work is in progress in exploring selective NMDA and/or
AMPA receptor antagonists as potential neuroprotective agents against such
degenerative diseases such as stroke and head injury, Alzheimer’s and other
chronic debilitating disorders.
EAA receptors can be divided into two distinct families based on similar
molecular structures, transduction mechanisms, and their pharmacological
profiles. This includes the ligand-gated
ion channel glutamate receptors (at present, there are at least three
distinct subtypes, i.e., NMDA receptor, AMPA (Quisqualate) receptor,
and KA receptor, based on their selective agonists) and the G-protein
coupled (metabotropic) receptors (mGluRs).
The metabotropic receptors are now recognized as a heterogeneous family
of G-protein coupled receptors that modulate excitatory synaptic transmissions
by a variety of cellular mechanisms (e.g., stimulating phosphoinositide
hydrolysis or inhibiting c-AMP formation).
NBQX is a selective AMPA receptor antagonist that protects against the
neurodegenerative effect of MPTP, a neurotoxin that selectively destroys
dopaminergic neurons in the brain (see pages 236 to 237 of your Foye’s
textbook for a discussion on how MPTP causes Parkinsonism in humans).
LY-215490 is a selective competitive NMDA receptor antagonist while
L-689, 560 is a non-NMDA antagonist that selectively binds to the glycine site
of the receptor. Both of these
compounds exhibit good neuroprotective activity and also have anticonvulsant
agents (Cognition Enhancers)
Aging, stroke, head injuries and neurodegenerative diseases accompanying old age such as Alzheimer's disease show symptoms of cognitive dysfunction. Loss of memory and dementia due to an aging brain poses a serious problem for older subjects and places a burden on society to take care of severely afflicted individuals. There is a lot of research activity in this area and several new strategies to combat these disorders are being pursued.
It is believed that cognitive dysfunction is due to neuronal degeneration
of the central cholinergic pathway in the cortex and hyppocampus (i.e.,
areas of the brain associated with cognition and learning).
Furthermore, it is also believed that postsynaptic M1
receptors remain relatively unchanged in Alzheimer’s patients while loss of
presynaptic cholinergic functions is realized in cognitive dysfunction.
Consequently, cholinergic agonists (particularly M1 agonists),
agents increasing acetylcholine levels and acetylcholinesterase inhibitors have
been pursued as potential chemotherapeutic agents.
Nootropics comprise mainly non-cholinergic agents that are being developed in order to cure the cerebral degeneration and to improve and protect cognition. Giurgea first coined the term nootropic and it describes agents that selectively affect higher, telencephalic integrative activity.
The basic criteria for a compound to qualify as a nootropic agent
were provided by Skondia. According
to his concept, the five basic criteria are enlisted as follows:
(1) It is necessary that the compound under consideration should not have any direct vasoactive effects.
The compound should have an effect on electroencephalographic activity.
The compound should be sufficiently non-polar to cross the blood brain
The compound should have minimal side effects.
The compound should enhance brain metabolic activity when administered to
It is sometimes difficult to tell when a particular compound belongs to
the nootropic class of drugs. But
the most important feature is that the compound must improve some kind of
cognitive function, usually defined as learning, acquisition, memory, or
retrieval. Also, the compound
should not have any adverse CNS side effects.
The more serious search for nootropic agents started with compounds
having a 2-pyrrolidinone moiety (Figure 3).
Piracetam is representative of this class of agents and because of its
favorable pharmacological profile; its clinical efficacy has been studied
As is evident from the structure, piracetam may be considered as a cyclic
analog of g-aminobutyric acid (GABA).
However, it is now certain that the pharmacological effect of piracetam is not
due to the release of GABA in vivo but
rather to its positive allosteric modulation of the L-glutamate responses on the
AMPA receptors. A pharmacological
tool to test the efficacy of nootropics is scopolamine.
The effect of scopolamine, a muscarinic antagonist, is to create
behavioral amnesia. Piracetam and
its analogues are able to reverse the effect of scopolamine at some doses.
In addition, piracetam is non-polar and passes through the blood brain
barrier. However the mechanism of
action of the 2-pyrrolidinone derivatives is yet to be elucidated.
It should be pointed out that a close structural analogue of piracetam,
has been approved in US in 1993 as a nootropic agent.
Interestingly, it has been demonstrated that 2-pyrrolidinone exists in
the plasma of man, rat, and mouse. Therefore,
derivatives such as piracetam and aniracetam may interact with an endogenous
substance to show the response.
PHAR 402, Dr. Lu
Amino Acid Receptor’s Agonists
Selective Agonists for NMDA Receptor:
Selective Agonists for KA Receptor:
Selective Agonist for AMPA Receptor:
There are chemical compounds that behave as either a positive allosteric
modulator or as negative allosteric modulators of AMPA receptors.
AMPA positive allosteric modulators are potential cognition enhancers
while AMPA negative allosteric modulators exhibited efficacy in reducing
infarction volume following focal ischemia in animal studies and thus have
potential cerebroprotective activity).
402, Dr. Lu
NMDA Receptor Antagonists
Competitive NMDA Antagonists
Note: APH exhibits anticonvulsant activity in a wide range of generalized or focal epilepsy without acute neurological side effects. However, it is poorly absorbed and high dose of APH produced undesirable muscle relaxation.
Competitive/Selective NMDA Antagonists
2. NON-Competitive NMDA Receptor Antagonists
PHAR 402, Dr. Lu
Handout # 5
Possible Sites of Interaction of Antiepileptic Drugs on Glutamate-mediated Transmission
Proposed Pharmacophore Model of known Anticonvulsants (Lamotrigine, Phenytoin, Carbamazepine, Sonisamide) to the Sodium Channel Binding Sites