PHAR 402, Dr. Lu

Handout # 1


Potential Antiepileptic Drugs Acting on Glutaminergic Receptors


Reading Assignments:


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).

5.                    Skinner, K.J., The Chemistry of Learning and Memory, A Special Report in Chemical & Engineering NEWS, October 7, 1991.

6.                    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).

 7.        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.


             Role of NMDA/AMPA Receptors in Learning and Other Cognition Processes




PHAR 402, Dr. Lu

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 activity. 






Nootropic 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.

                (2)           The compound should have an effect on electroencephalographic activity.

                (3)           The compound should be sufficiently non-polar to cross the blood brain barrier.

                (4)           The compound should have minimal side effects.

    (5)                     The compound should enhance brain metabolic activity when administered to patients.

                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 extensively.



Figure 3.

                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, pramiracetam (Remenâ, Neupraminâ, Pramistarâ) 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

Handout # 3                                         


Excitatory Amino Acid Receptor’s Agonists


Endogenous Agonists: 


Selective Agonists for NMDA Receptor:



Selective Agonists for KA Receptor:


Selective Agonist for AMPA Receptor:



Note:      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).

PHAR 402, Dr. Lu

Handout # 4                          NMDA Receptor Antagonists


1.                   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.


Newer 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