Targets of Psychopharmacological Drug...

Targets of

Psychopharmacological

Drug Action

(page 33 in syllabus)

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry

University of California, San Diego School of Medicine

Honorary Visiting Senior Fellow, Cambridge University, UK

Sponsored by the Neuroscience Education Institute

Additionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported solely by the sponsor, Neuroscience Education Institute.

Faculty Editor / Presenter

Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at

the University of California, San Diego School of Medicine, and an honorary visiting

senior fellow at the University of Cambridge in the UK.

Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind,

Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion,

Servier, Shire, Torrent

Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail,

Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo,

Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck,

Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis,

Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott,

Sunovion/Sepracor, Valeant, VIVUS,

Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer,

Sepracor/Sunovion, Servier, Wyeth

Individual Disclosure Statement

Learning Objectives

• To explore transporters as drug targets

• To explore G protein-linked receptors as drug

targets

• To explore ligand-gated ion channels as drug

targets

• To explore voltage-sensitive ion channels as

drug targets

Transporters and G Protein-Linked

Receptors as Targets of

Drug Action

Major Targets of Psychopharmacologic

Drug Action

12 transmembrane

region transporter

~ 30% of psychotropic drugs

7 transmembrane region

G protein linked

~ 30% of psychotropic drugs

Other Targets of

Psychopharmacologic Drug Action

ligand-gated ion channel

~ 20% of psychotropic

voltage-gated ion channel

enzyme

Targets of

Psychopharmacological Drug Action

• Transporters

• G protein-linked receptors

• Ligand-gated ion channels

• Voltage-sensitive ion channels

• Enzymes

Presynaptic transporters are a primary mode of

inactivation for which of the following?

1. Monoamines

2. Amino acid neurotransmitters such as GABA and

glutamate

3. Neuropeptides

4. 1 and 2

5. 1, 2, and 3

Pretest Question 1

Pretest Question 2

The vesicular monoamine transporter 2 (VMAT2)

is utilized by which neurotransmitter?

1. Serotonin

2. Norepinephrine

3. Dopamine

4. 2 and 3

5. 1, 2, and 3

Monoamine Transporters

presynaptic neurons

SERT NET DAT

5HT NE DA

VMAT 2 VMAT 2 VMAT 2

serotonin (5HT)

vesicles

proton pump

VMAT 2

ATPase

add fluoxetine

fluoxetine (Prozac)

Acetylcholine and Choline Transporters

presynaptic neuron

choline

transporter

choline

GABA Transporters

presynaptic neuron

glial cell

Glutamate Transporters

presynaptic neuron

glial cell

postsynaptic neuron

glutamine

VGluT 1

Targets of

• Transporters

• Enzymes

Pretest Question 3

An antagonist is the opposite of an agonist.

1. True

2. False

The Agonist Spectrum

agonist

partial agonist

antagonist

inverse agonist

No Agonist: Constitutive Activity

Full Agonist: Maximum Signal Transduction agonist

"Silent" Antagonist: Back to Baseline,

Constitutive Activity Only, Same as No Agonist

antagonist

Partial Agonist:

Partially Enhanced Signal Transduction

partial agonist

Pretest Question 4

A partial agonist can be a net agonist when

neurotransmission is deficient but a net

antagonist when neurotransmission is

excessive.

1. True

2. False

FULL AGONIST —

light is at its brightest PARTIAL AGONIST —

light is dimmed but still shining

NO AGONIST —

light is off

inverse agonist

Inverse Agonist: Beyond Antagonism;

Even the Constitutive Activity Is Blocked

Agonist Spectrum

no agonist or silent antagonist

partial agonist

agonist

inverse agonist

Ion Channels and Enzymes

as Targets of

Drug Action

Targets of

• Transporters

• Enzymes

The Agonist Spectrum

partial agonist

antagonist

agonist

inverse agonist

Pretest Question 5

A receptor will stop responding to an agonist:

1. When the agonist stops binding to it

2. When the receptor becomes desensitized

3. When the receptor becomes inactivated

4. 1 and 3

5. 1, 2, and 3

Channel in

resting state

Channel

closed

Channel

desensitized

Channel

inactivated

Opening, Desensitizing, and Inactivating of

Ligand-Gated Ion Channels by Agonists

Desensitized state activated by prolonged agonist

Resting state

Open state activated by acute agonist

Inactivated state not immediately reversed by removal of agonist

order of hours

agonist

GABA benzodiazepine

positive

allosteric

modulation

open open

further

resting

GABA A

receptors

Benzodiazepines: Indirect Effect on

GABA Neurotransmission

Targets of

• Transporters

• Enzymes

Pretest Question 6

When voltage-sensitive sodium channels are

open and activated, the flow of sodium is:

1. Into the neuron

2. Out of the neuron

The Pore of a Voltage-Sensitive Ion Channel

Has 6 Transmembrane Regions

outside the cell

inside the cell

1 2 3 4 5 6

The Loop Between Regions 5 and 6 is

an Ionic Filter

1 2 3 4 5 6 1 2 3 4 5 6

Voltage-sensitive sodium channel (VSSC) Voltage-sensitive calcium channel (VSCC)

outside the cell

inside the cell Na+

Four Subunits Combine to Form the Alpha Pore Subunit, or Channel, for Sodium of a

VSSC (Voltage-Sensitive Sodium Channel)

outside the cell

inside the cell pore inactivation

I II III IV

outside the cell

inside the cell

pore inactivation

Structure of Voltage-Sensitive Sodium

Channels (VSSCs)

Pretest Question 7

Which of the following has evidence that it binds

the alpha subunit of voltage-sensitive sodium

channels?

1. Gabapentin

2. Pregabalin

3. Lamotrigine

4. 1 and 2

5. 1, 2, and 3

inside the cell

outside the cell

Possible Binding Sites for Certain

Mood Stabilizers on VSSCs

lamotrigine

carbamazepine

oxcarbazepine

Pretest Question 8

The alpha-2 delta subunit of voltage-

sensitive calcium channels is believed to

help regulate opening and closing of the

voltage-sensitive calcium channel.

1. True

2. False

VSCCs (Voltage-Sensitive Calcium Channels) Have

Multiple Associated Regulatory Proteins

outside the cell

inside the cell

Opening a Presynaptic Voltage-Sensitive N or P/Q

Calcium Channel Triggers Neurotransmitter Release

glutamate

vesicle

Structure of Voltage-Sensitive

Calcium Channels (VSCCs)

Site of Action of Alpha-2 Delta Ligands as Selective Inhibitors of Presynaptic Voltage-Sensitive N and

P/Q Calcium Channels

= alpha-2 delta

ligand

closed

Molecular Action of Alpha-2 Delta Ligands

Pretest Question 9

Which of the following are involved in regulating

neurotransmission via excitation-secretion

coupling?

1. Voltage-sensitive sodium channels

2. Voltage-sensitive calcium channels

3. Both 1 and 2

4. Neither 1 nor 2

Nerve Impulse Propagation in Presynaptic Neuron:

Serial Opening of VSSCs (Voltage-Sensitive Sodium Channels)

reception

integration chemical encoding

electrical encoding

signal propagation

signal transduction

Presynaptic Release of Neurotransmitter by Excitation-Secretion

Coupling: VSSCs, VSCCs, and Synaptic Vesicles

reception

integration chemical encoding

electrical encoding

signal propagation

signal transduction

action

potential neurotransmitter

vesicle

VSSC VSCC

Synaptic Neurotransmission

With Vesicular Release

Range of Synaptic Neurotransmission

Summary

• The major targets of psychopharmacologic drug

action are transporters and G protein-linked

receptors

• Ion channels, both ligand gated and voltage

sensitive, are also important targets of

psychopharmacologic drug action

• Enzymes also are the targets of some important

psychopharmacological drugs

Targets of Psychopharmacological Drug...

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