PHAR 402, Dr. Lu

Handout # GABA-1               

                       GABAergic Synapse and Potential Sites of Drug Action

                         

Sites of Drug Actions:

1.         Biosynthesis of GABA - Stimulation or inhibition of L-glutamic acid decarboxylase (GAD).

2.         Release of GABA

3.         Postsynaptic Receptors - GABAA, GABAB receptors agonists and antagonists, BZD receptors (agonists, inverse agonists & antagonists), Drugs acting at the neurosteroid binding sites, Drugs binding to the chloride channel proteins.

4.         GABA Re-uptake Inhibitors.

5.         Autoreceptors - Agonists & antagonists

6.         GABA Transaminase Inhibitors

PHAR 402, Dr. Lu

Handout # GABA-2                Mechanism of GABA Transaminase Catalyzed Reaction

Handout # GABA-3   

                                  Model of the GABA Receptor-BZD Receptor-Chloride Channel Complex           

Table 1.                   Benzodiazepine Receptor Subtypes

_____________________________________________________________________________________

Receptor

designation                              localization                                              pharmacological characteristics        

    BZ1 (w1)              brain: primarily cerebellar neurons                         high affinity (10-9M) for CL218872;

                                                                                                                high affinity for clonazepam;

                                                                                                                negligible affinity for Ro 5-4864;

                                                                                                                binding enhanced by etazolate & GABA, bicuculline sensitive;

                                                                                                                ? selectively labeled by b-CCM

     BZ2 (w2)             brain: primarily hippocampus                                low affinity for CL 218872;

                                                                                                                high affinity for clonazepam

                                                                                                                binding enhanced by etazolate, GABA pentobarbital, bicuculline sensitive; low affinity for b-CCE

    BZ3 (w3)             brain                                                                        low affinity for CL218872;

                                                                                                                insensitive to GABA/bicuculline and etazolate; binding enhanced by barbiturates;

                                                                                                                high affinity for b-CCE

Anticonvulsant       brain synatosomal                                                   low affinity for BZDs;

                                                                                                                good correlation with BZD antagonism of electric-shock induced convulsions

peripheral                peripheral tissues: liver, kidney, etc.                      no correlation with clinical actions of BZDs, high affinity for Ro 5-4864,

                                                                                                                low affinity for clonazepam; binding not GABA-stimulated

PHAR 402, Dr. Lu

Handout # GABA-4

                                   GABA Receptor Agonists and GABA Uptake Inhibitors


Study Questions:

 

1.  Can you envision a GABA receptor - bound conformation for the GABA molecule?

2.  Explain why 4,4-dimethyl ACA exhibits neither GABA receptor agonist activity nor GABA uptake inhibitory activity?

3.  Show by chemical equation how progabide is converted to GABA in vivo?


PHAR 402, Dr. Lu

Handout # GABA-5

 

                                       GABA Receptor Antagonists & Other GABA Derivatives

                         

Study Questions:

 

1.  Can you see an alternative explanation for how Gabapentin might work to exert its anticonvulsant activity?

2.   Explain why Gabazine is a selective GABAA antagonist?

3.   Recently, the brain uptake and pharmacological properties of  LGV has been reported [J. N. Jacob et al. J. Med. Chem., 33, 733-736 (1990)].  Normally, GABA is virtually excluded from entering the brain [i.e., the brain penetration index (BPI) for GABA is approximately 1%].  However, the brain uptake study of LGV indicated that it had a BPI value of 97%.  Provide one reason for this difference.  Explain, with your knowledge of drug design principles, why this compound may be superior to progabide as an anticonvulsant.

                                                       


PHAR 402, Dr. Lu

Handout # GABA-6                Drugs Binds to the Benzodiazepine Receptors

 

1.  Benzodiazepine Receptor Agonists

 

2.  Benzodiazepine Receptor Antagonists (used for BZD overdose only)

                

3.  Inverse Agonists (CNS convulsants)

 

 

4.  Drugs Acting on the Diazepam Binding Inhibitor Receptor Binding Site

 

PHAR 402, Dr. Lu

Handout # GABA-7                Drugs Interact with the Barbiturate/Picrotoxinin Binding Site

1.  CNS Stimulants (i.e., these compounds block chloride channel opening)

                              

2.  Barbiturates (Positive allosteric effectors of GABA receptor, hypnotic-sedatives, anticonvulsants, and anxiolytics)

 3.  Pyrazolopyridines (Non-barbiturate anxiolytics)