Introduction to the Pharmacology of CNS Drugs

Voltage-gated Channel

Voltage-gated Channel

Sodium Channels Potassium Channels Calcium Channels

Ligand-gated Channel

Nicotinic ACh receptor GABAA receptor Glycine receptor AMPA receptor

Sodium channels

Tetrodotoxin TTX Batrachotoxin BTX

Potassium Channels

Apamin Charybdotoxin

Calcium channels

Omega conotoxin Agatoxin

Nicotinic CH receptor

alpha-bungarotoxin

GABAA receptor

picrotoxin

Glycine Receptor

Strychnine

AMPA receptor

Philanthotoxin

Source of Tetrodotoxin

Puffer fish

Source of Batratoxin

colombian frog

Source of Apamin

honeybee

Source of Charybdotoxin

scorpion

Source of Omega conotoxin

pacific cone snail

Source of agatoxin

funnel web spider

Source of alphabungarotoxin

marine snake

Source of picrotoxin

south pacific plant

Source of strychnine

indian plant

Source of philanthotoxin

wasp

Mode of Toxin Action: Tetrodotoxin

blocks channel from outside

Mode of Toxin Action: Batrachotoxin

Slows inactivation, shifts activation

Mode of Toxin Action: Apamin

Blocks small Ca-activated K channel

Mode of Toxin Action: Charybdotoxin

blocks big Ca-activated K channel

Mode of Toxin Action: Omega conotoxin

blocks n-type channel

Mode of Toxin Action: Agatoxin

blocks p-type channel

Mode of Toxin Action: alpha bungarotoxin

irreversible antagonist

Mode of Toxin Action: picrotoxin

blocks channel

Mode of Toxin Action: strychnine

competitive antagonist

Mode of Toxin Action: philanthotoxin

blocks channel

↑Na, ↑Ca , ↓K

EPSP

↑K, ↑ Cl postsynaptic, ↓Ca presynaptic

IPSP

depolarizing potential, intracellular less negative

EPSP

hyperpolarizing potential, intracellular more negative

IPSP

E1 + E2

Spatial summation

E1 E1

Temporal summation

large myelinated rapidly conducting fibers Excitability of CNS upper lower motor primary secondary tertiary sensory

Hierarchial System

located in small discrete nuclei different parts of the brain

Diffuse/ Nonspecific neuronal system

1. Action potential in presynaptic fiber

2. Synthesis of transmitter

3. storage

4. metabolism

5. release

6. reuptake into the nerve ending or uptake into a glial cell

7. degradation

8. receptor for the transmitter

9. receptor induced increase or decrease in ionic conductance

10. retrogade signaling

sites of drug action

Excitatory: ↓ K conductance, ↑IP3 DAG

pirenzepine, astropine [acetylcholine]

Inhibitory: ↑ K conductance, ↓cAMP

atropine, methoctramine [acetylcholine]

Excitatory: ↑ cation conductance

dihydro-b-erythroidine, alpha bungarotoxin [acetylcholine]

Inhibitory: ↑ cAMP

phenothiazines [dopamine]

Inhibitory (presynaptic): ↓ Ca Inhibitory (postsynaptic): ↑ K conductance ↓ cAMP

phenothiazines, butyrophenones [dopamine]

Inhibitory: ↑ Cl conductance

bicuculline, picrotoxin [GABA]

Inhibitory (presynaptic): ↓Ca conductance Inhibitory (postsynaptic) ↑K conductance

2OH saclofen [GABA]

Excitatory: ↑cation conductance particularly Ca

2 amino 5 phosphonovalerate dizocilpine [Glutamate]

Excitatory: ↑Cation conductance

NBQX [Glutamate]

Excitatory: ↑cation conductance

ACET [Glutamate]

Inhibitory (presynaptic): ↓Ca conductance ↓cAMP Excitatory: ↓K conductance ↑IP3 Dag

MCPG [Glutamate]

Inhibitory: ↑Cl conductance

strychnine [Glycine]

Inhibitory: ↑K conductance, ↓cAMP

metergoline, spiperone [Serotonin]

Excitatory: ↓K conductance ↑IP3 Dag

ketanserin [Serotonin]

Excitatory: ↑cation conductance.

ondansetron [Serotonin]

Excitatory: ↓K conductance

piboserod [Serotonin]

Excitatory: ↓K conductance ↑IP3 DAG

prazosin [Norepinephrine]

Inhibitory (presynaptic): ↓ Ca Inhibitory:↑ K conductance ↓cAMP

yohimbine [Norepinephrine]

Excitatory: ↓ K conductance ↑ cAMP

atenolol, practolol [Norepinephrine]

Inhibitory: may involve in ↑ electrogenic sodium pump ↑ cAMP

butoxamine [Norepinephrine]

Excitatory: ↓ K conductance ↑ IP3 DAG

mepyramine [histamine]

Excitatory: ↓ K conductance, ↑ cAMP

ranitidine [histamine]

Inhibitory autoreceptors

thioperamide [histamine]

Inhibitory (presynaptic): ↓ Ca conductance ↓ cAMP Inhibitory (postsynaptic): ↑ K conductance ↓ cAMP Inhibitory (postsynaptic): ↑ K conductance ↓ cAMP

Naloxone [opioid peptides]

Excitatory: glutamate co-release

Suvorexant [orexins]

Excitatory: ↓K conductance ↑ IP3 Dag

Aprepitant, Saredutant, Osanetant [Tachykinins]

Inhibitory (presynaptic): ↓Ca conductance ↓cAMP

Rimonabant [Endocannabinoids]

Table 1

Some toxins used t o characterize ion channels.

Acetylcholine

Anatomy, Receptor, Mechanisms

Dopamine

Anatomy, Receptor, Mechanisms

GABA

Anatomy, Receptor, Mechanisms

Glutamate

Anatomy, Receptor, Mechanisms

Glycine

Anatomy, Receptor, Mechanisms

Serotonin

Anatomy, Receptor, Mechanisms

Histamine

Anatomy, Receptor, Mechanisms

Norepinephrine

Anatomy, Receptor, Mechanisms

Opoid peptides

Anatomy, Receptor, Mechanisms

Orexins

Anatomy, Receptor, Mechanisms

Tachykinins

Anatomy, Receptor, Mechanisms

Endocannabinoids

Anatomy, Receptor, Mechanisms