Download GABA Recognition Site

GABA Receptors and
Cognition: Perspectives
for Drug Development
S. J. Enna, Ph.D.
Summer School of Neuroscience
Catania, Italy
July 11, 2015
γ-Aminobutyric Acid
(GABA)
- Widely Distributed Throughout the CNS
- 30-40% of All CNS Neurons Are GABAergic
- Major Inhibitory Neurotransmitter
Principles of GABA
Pharmacology
-
Attractive Target Because of Importance in CNS
Function
- Generalized Activation Decreases CNS Activity
•
•
•
Sedation
Hypnosis
Cognitive Impairment
- Generalized Inhibition Increases CNS Activity
•
•
Anxiety
Seizures
- Selective Manipulation of Receptor Subtypes Are
Essential for Therapeutic Benefit
GABA Receptors
GABAA
- Pentameric Ligand-Gated Ion
Channel
GABAB
- G Protein-Coupled (Go/Gi)
GABAA
Receptor
GABA Recognition Site Muscimol, THIP
Benzodiazepine Site
Diazepam, Zolpidem
Ion Channel Site
Phenobarbital
Cellular Response:
Pharmacology:
Structural Properties:
Bicuculline
Flumazenil (Anexate)
Picrotoxin
Hyperpolarization (  Cl- conductance)
Agonists - Anxiolytics, Hypnotics
Antagonists – Convulsants
Pentameric Ligand-Gated Ion Channel
Eighteen Subunits
α1-6; β1-3; γ1-3 ; δ1; ε1; θ1; ρ1-3
α2 β2 γ2 (60%)
Cellular Localization of
GABAA Receptors
From Rudolph, U. and Knoflach, F., Nature Reviews Drug Discovery, 2011
Benzodiazepine-Sensitive
GABAA Receptor
Benzodiazepine Site
GABA Site
β
γ
α
α β
Ion
Channel
DEFINITIONS
– Orthosteric Compound –
Attaches to the receptor recognition site
– Allosteric Compound –
Attaches to a receptor component
distinct from the recognition site
Allosteric vs. Orthosteric Drugs
- Allosteric Effects are Saturable in
Physiological Range
o
Act only in the proximity of released transmitter
- Greater Tissue Selectivity
o
Act only in tissues where transmitter is active
- Greater Receptor Subtype Selectivity
o Variable effects on receptor affinity and efficacy
GABAB Receptor
Orthosteric Site
Allosteric Site
Adapted from Urwyler, S., Pharmacological Reviews, 2011
GABAB Receptor Pharmacology
• Representative Allosteric Compounds:
CGP7930
CS39783
o Reduce the sedative/hypnotic response thresholds to baclofen without
displaying effects themselves
o When administered alone they display anxiolytic, but not
antidepressant, effects in laboratory animals without causing sedation,
muscle relaxation or cognitive dysfunction
Inverse Agonist
From https://en.wikipedia.org/wiki/Inverse_agonist
Neurotransmitter and
Enzyme Modifications in
Alzheimer’s Disease
From Enna, S.J., et al, Brain Research, 1976
Effect of RO4938581 on
Scopolamine-induced
Impairment of the DMTP Task
From Ballard, T.M., et al, Psychopharmacology, 2009
RO4938581 Effect in
Cynomolgus Macaques
Data are presented as mean ± SEM (n=12)
** p < 0.01 vs. vehicle (V)
From Ballard, T.M., et al, Psychopharmacology, 2009
Subtype Selective GABAA
Receptor Compounds
From Rudolph, U. and Knoflach, F., Nature Reviews Drug Discovery, 2011
Effect of SGS742 in Step-Down
Passive Avoidance in Mice
*** p < 0.001: generalized two-tailed
Wilcoxon test
From Froestl. W., et al, Biochemical Pharmacology, 2004
Summary and Conclusions
- Cognition is Subject to GABAergic
Regulation
- GABA Receptor Subtype-Selective Agents
Needed to Enhance Cognition
- Allosteric Modulators and Partial Agonists
and Antagonists Are Required to Minimize
Side Effects and Enhance Efficacy