Ferchmin 2014
Introduction to Neuropharmacology
Pharmacology is the science that study the interaction of drugs with
biological systems either in vivo, ex vivo or in vitro. Pharmacology comes from
pharmakon, poison or drug in Greek. In Spanish there is a handy word farmaco
that is lacking in English.
Drug is defined as any natural or synthetic molecule which causes an effect on
biological systems. If substances have medicinal properties, they are
considered medicines or pharmaceuticals.
Pharmacology includes the study of synthesis and drug design, mechanism of
action, signal transduction, drug interactions, toxicology, therapy, and medical
applications.
The three branches of pharmacology are pharmacodynamics, pharmacokinetics
and toxicology.
Pharmacodynamics, broadly defined, studies the effects of drugs on biological
systems by interactions with receptors.
Pharmacokinetics studies the absorption, distribution, metabolism, and
excretion of chemicals from the biological systems.
Toxicology studies the toxic effects of drugs. It must be kept in mind that all
chemicals are toxic and even lethal at high dose.
Neuropharmacology is pharmacology applied to the
nervous system
We will summarily address the following subjects
Definition of basic concepts: agonists, antagonists, and positive modulators; efficacy and
potency (EC50, IC50).
An overview of the main neurotransmitter systems in the brain: glutamate, GABA,
acetylcholine, etc.
There are four main protein targets with which drugs can interact:
enzymes (e.g. sarin that inhibits acetyl cholinesterase), membrane carriers,
ion channels (e.g. nimodipine and voltage-gated Ca2+ channels) and
receptors. Receptors interact with agonists, antagonists, partial agonists
and inverse agonists.
The binding of drugs with “inert” proteins can also have an important effect.
Definitions
KD: The equilibrium dissociation constant represents the concentration of
ligand occupying half of the maximum receptor population. KD is a measure
of affinity. Interestingly, the smaller the KD the higher the affinity.
Potency of a drug is the concentration which elicits a given response often
relative to other drug. More precisely, potency is the concentration that
produces 50% of the maximum response. It can also be defined as
effective dose 50% or ED50. Potency is equivalent to the Km of enzymes.
Efficacy is the maximum response produced by a particular agonist.
Efficacy is equivalent to Vmax in enzymes.
Clearly, the concepts used in pharmacology and presented here are
borrowed from the Michaelis–Menten enzyme kinetics model.
There are several manners to do DRC.
Often a cumulative DRC is the most practical
Copyright © 2004 Allyn and Bacon
“Review” of receptors
No formal system for the classification of receptors exists. A receptor is usually defined
as a protein that binds a relatively specific molecule called the ligand. The binding of the
ligand to its receptor has a functional effect.
The two main types of receptors could be defined as
ionotropic and metabotropic.
The ionotropic receptors have intrinsic channels that allow currents of either cations or
anions. In general, the cation selective receptors are depolarizing while the anion selective
ones are hyperpolarizing. Receptors with cationic channels conduct Na+, K+ or Ca2+ ions.
Receptors with anionic channels conduct Cl- and to a lesser degree HCO3-.
Some ionotropic receptors are both, ligand and voltage gated. Directly or indirectly all ionotropic
receptors are modulated by the voltage across the membrane.
Metabotropic receptors, after binding the ligand cause a metabolic change in the cell that
often, but not always, mediate indirectly modulation of ion channels usually through second
messenger systems.
Metabotropic receptors are slower than ionotropic receptors because of the nature of the
mechanism that mediates the physiological effect. Therefore, the skeletal voluntary muscles
have nicotinic receptors while the smooth muscles have muscarinic receptors.
The prototypic metabotropic receptor is the muscarinic acetylcholine receptor and the prototypic
ionotropic receptor is the nicotinic acetylcholine receptor.
In the brain the main excitatory (depolarizing) transmitter is glutamate.
Glutamate binds to several metabotropic and several ionotropic receptors. The
main ionotropic receptor is the AMPA receptor. AMPA is an abbreviation of (±)alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid, obviously this is the
last complete name that is shown here. You will have to put up with
abbreviation only. The other glutamate ionotropic receptor is the kainate
receptor. AMPA is a synthetic compound and kainate is an antihelminthic
Japanese folk remedy. They are tools to differentiate subtypes of receptors, they
are specific for a specific subtype of glutamate receptor. Neither AMPA nor
kainate are endogenous!!!! They are just tools. Both AMPA and kainate have
several subtypes that differ in ion selectivity and other parameters. Some
subtypes of AMPA and kainate are more permeant to Ca2+ than others. The
NMDA type of glutamate receptor is a ligand and voltage gated receptor. Its
natural (endogenous) ligands are: spermine, glycine and glutamate. Glutamate
is the actual neurotransmitter. The importance of spermine and glycine varies
with the subtype of the NMDA receptor. The NMDA receptor is normally blocked
with the Mg2+ ion. Only a considerable degree of depolarization removes the
inhibition due to Mg2+ and allows the NMDA receptor to conduct Na+, K+ and
Ca2+.
NMDA is a synthetic molecule that specifically binds the glutamate
receptor of NMDA type. NMDA stands for N-methyl-D-aspartate. Try to draw this
formula.
The most common amino acid neurotransmitters are: Glutamate; Gamma-aminobutyric acid (GABA) and Glycine.
NMDA receptor: A specialized ionotropic glutamate receptor that controls a calcium channel
that is normally blocked by Mg2+ ions. It has several other binding sites for ≠ ligands.
AMPA receptor is an ionotropic glutamate receptor that controls a sodium channel. It is
stimulated by AMPA and blocked by CNQX. Both compounds are synthetic. AMPA receptor is the
most common glutamate receptor in the CNS.
Glutamatergic transmision
What is excitotoxicity?
Epilepsy and excitotoxicity can be stopped or ameliorated by
hyperpolarizing currents mediated by inhibitory transmitters.
GABA (γ-aminobutyric acid) and glycine are two main hyperpolarizing
and therefore inhibitory neurotransmitters. Inhibition of GABA
transmission induces seizures.
GABA is synthesized from Glutamate by the enzyme Glutamic Acid
Decarboxylase (GAD) which is a marker of GABAergic neurons.
Strychnine, a glycinergic antagonist, also causes seizures and for that
purpose was used to control rodents, dogs and others.
GABAergic transmission
muscimol
There are two main type of GABA receptors: GABAA (ionotropic) and GABAB
(metabotropic)
GABAA receptor consists of a channel for Cl-. Drugs that interact with GABA are:
Muscimol (agonist); Bicuculline (antagonist); Pentylenetetrazol (antagonist)
Benzodiazepines*; Barbiturates* and Ethanol are positive modulators. They
activate the receptor together with GABA. There is no effect in absence of
GABA
GABAB receptors (GABAB R) are metabotropic transmembrane receptors for
GABA that are linked via G-proteins to potassium channels.
Baclofen is an agonist for GABAB receptors and it is used as a muscle relaxant.
Glycine
Glycine is an amino acid and a hyperpolarizing neurotransmitter
in the spinal cord and some other areas of the CNS where it
binds to strychnine sensitive sites (strychnine binding sites).
This glycine-binding site at the glycine receptor is different from
the glycine-binding site at the NMDA receptor.
Strychnine: A direct antagonist for the glycine receptor is a poison
because it causes fatal convulsions.
Acetylcholine (Ach)
Acetylcholine: Otto Loewi, 1921. Was the first neurotransmitter
discovered.
The cholinergic pharmacology is well studied and has many practical
applications.
Botulinum toxin: Prevents the release of ACh from nerve terminals.
Black widow spider venom: A poison produced by the black widow spider
that triggers the release of acetylcholine.
There are many inhibitors of acetylcholine esterase including warfare
never agents and insecticides that cause a cholinergic a crisis by
overstimulation
Hemicholinium: A drug that inhibits the uptake of choline.
Vesamicol inhibits the reloading of vesicles with acetylcholine.
The two cholinergic receptor families are the nicotinic and the muscarinic
receptors
Nicotinic acetylcholine receptors
A model for AChR 3-D structure indicating possible locations for the binding-sites for non-competitive inhibitors and
positive modulators. Ovals indicate the binding location of channel blockers (black), competitive ligands (blue), agonist sites
(red) and positive modulators (grey oblique). Adapted from Hansen and Taylor, 2007.
There are several nicotinic receptor subtypes. They
are all pentamers and share a common design but
have different subunits.
7
7
Cationic
pore
7
7 7
Homomeric
α7 neuronal
nAChR
2
4
Cationic
pore
2
4 2
Heteromeric
α4β2
neuronal
nAChR

1
Cationic
pore
1


The adult
muscle
receptor
These receptors are activated and desensitized by nicotine to a different
degree in a subtype and agonist concentration dependent manner.
Neuronal type nAChR present in physiologically
significant concentration in hippocampal area CA1
α7
Muscle type nAChR
α7 α7
α7
α7
α7
Inhibited by α7-bungarotoxin,
methyllycaconitine and 4R,
the tobacco cembranoid
α4β2
α4 β2
β2
α4 β2
Inhibited by
dihydro-β-erythroidine
α7 nAChR
 Homomeric
 More permeable to
calcium than other nAChRs
 Functions: stabilizing
synapse formation during
development; learning and
memory; neuronal survival,
etc.
Muscarinic receptors were originally defined by their activation by
muscarine derived from the mushroom Amanita muscaria that was used
to kill flies. In man it causes convulsions and death. The muscarinic
receptors are part of the family of G-protein-coupled. Muscarinic
receptors are involved in many physiological functions like heart rate,
contraction of smooth muscles and control of neuronal excitability. There
are five types of muscarinic M1-M5.
M1, M3 and M5 subtypes cause the activation of phospholipase C,
generating two secondary messengers (IP3 and DAG) eventually leading
to an intracellular increase of calcium, while M2 and M4 inhibit adenylate
cyclase, thereby decreasing the production of the second messenger
cAMP. The M1 receptors increase neuronal excitability and for this
reason are involved in cognitive enhancement. However excessive
stimulation of M1 like in case of warfare nerve agent poisoning it causes
central seizures and fatal brain damage.
Copyright © 2004 Allyn and Bacon
Warning:
In this introductory lecture the exciting fields of catecholamines, serotonin
and other neurotransmitters were not discussed. You will learn this topics
later if you will need them.
With reference to the next slide.
Agonist is the compound that causes the effect of the natural ligand.
Antagonist is the compound that blocks the effect of the natural ligand.
We assume that agonist and antagonist bind to the receptors
to produce their effect. However, old fashion, not very molecular
pharmacologist often call agonists or antagonist drugs that affect synthesis
or break down of the transmitter.
Copyright © 2004 Allyn and Bacon
Copyright © 2004 Allyn and Bacon
The non-official first law of pharmacology states that:
Some drugs are selective but none is specific.
The forbidden first law of clinical pharmacology states that:
The probability of a clinician to prescribe a drug is inversely
proportional to the $@!#^&*(^%! of the representative of the
pharmaceutical company and directly proportional to other
advertising gimmicks of the pharmaceutical company