8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 1/12

Neuro 413

2/18/14

UNIT 3 PART A:

Drug effect-actions of the drug at receptor

Max effect- when receptor is fully occupied

Potency-ED50

Accesibility of drug to receptor

Affinity to receptor

(fill)

Affinity- Measure of tightness in which a drug binds to a receptor

-Efficacy= Bound, thus measuring the ability to make a biological effect

-Endogenous substance

- Also know as intrinsic

D+R< DR

>

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 2/12

K= rate of disassociation/ association

-With each other that is

K1-Rate of association

High Affinity- Bind to receptor (larger value of K1) relative to dissociation (small

value of K1)-> Greater tendency

KD- Equilibrium dissociation constant

-amount of drug needed to occupy 50% of the receptors

Small KD=higher affinity-value is higher than value for Diss

Less of the drug is needed to occupy 50% of the receptors

Units=concentration (M, mM, etc)

Drug given at KD- at 50% of receptor

Less drug is needed thus

ED50 does not equal KD

Drugs differ in their ability to produce a conformational change

Efficacy-> Receptor occupancy

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 3/12

-Ability of drug to activate receptor

--> Thus a conformational change occurs

--> (fill)

Agonist- Ligand that has affinity and efficacy at the receptor

-> Leads to a biological effect

-> Full= complete

-> Partial-> Not able to complete the bio effect

Antagonist- Same as Agonist, but has no efficacy

-Square block in a round hole

-> Competitive- Prevents other things from affecting the receptor. Same location

or similar to the place where NT bind, thus preventing an effect. Up the dosage,

and it will outcompete the NT

-> non competitive - Changes the receptor to fit the antagonist, but not the

original NT. Different site, thus no matter the dosage it will not activate the

receptor

So where are they binding at the receptor

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 4/12

More Complex effects- Partial agonist

-> Does not reach the max activity

-> No matter how much is given

Inverse agonist-> Reduces the total constitutive effect

->Normally some activity (endogenous) is occurring. Level of activity is prevented

due to binding to receptor and making the receptor inactive. Causing the receptor

to change. -> G protein

Individual receptor now

6 main types

1. Ionotropic

->Complete receptor protein is composed of 4-5 subunits

-> Make a funcitonal receptor

- Tetramer or Pentamer

-Form a pore (centralized) thus allows Ion movement

-> 1 or more binding sites for ligands

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 5/12

(usually at N terminus)-> changes membrane potential

Each subunit has 4 transmembrane domains (TMDs)-> unique AA makeup each

-M1 to M4

GABAa has 5 subunits-> permeable to chloride

Break

2. G protein receptor

- Metabotropic receptors

--> Most common in the brain ( > 1000)

1 Protein subunit site with 7 TMDs: Binding site-> coils of the AA sequence

Ligand binding does not equal Ion channel opening

-> Leads to activation of G-protein

Functional receptor is called a Dimer

- 2 GPCR subunits combined together

-Dimers equal a greater chance for a biological effect.

G protein Coupled Receptor

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 6/12

G- Guanine

A dissociable heterotrimeric complex

GDP bound alpha subunit

Beta and Gamma subunits

4 Families of subunits: Gi/o, Gs, Gq, G12/13<- Alpha

Basal state- GDP bound α subunit and the Beta/ Gamma complex are associated 

Ligand (agonist) binds

Conformational change occurs when agonist binds

-β/Gamma can influence different enzymes, etc. <- Affectors

α can also influence other places

Not meaningful if termination is possible

- GTP turing back into GDP

--> Activity of GTPases

-> Regulators of G-protein signaling (RGS)

Effectors can have GTPase activity

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 7/12

Return to Basal state

- GDP bound (fill)

Stimulating of inhibiting the opening of Ion channels = G protein gated ion

channel (Calcium and Potassium)

Stimulating of inhibiting effectors which in turn act on 2nd messengers

-2 main effector enzymes- Adenylyl Cyclase(AC) and Phospholipase C(PLC)

2nd messenger pathways

Effectors lead to synthesis or breakdown of 2nd messengers

- Cyclic AMP ( cAMP)

-IP3 and DAG

These then activate protein kinases

-Phosphorilation of proteins then change of their function

Can also Phospholylate proteins in the nucleus that turn off/on genes

Usually hours or longer (permanent)

transporters

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 8/12

- Plasma membrane transporters

-remove, or release molecules across the cell

- Sodium chloride dependant Trans.

--> 12 TMD

--> cotransport NA+ and CL with the NT -> Dopamine, Norepinephrine and

Serotonin

Sodium dependant transporters

6, 8 or 10 (?) TMDs

-co-transport of sodium and potassium

--> Glutamate

Vesicular membrane transporters

-Dependant on the movement of H+

-Localized on vesicles

- Cytoplasm to vesicles

trk Receptor

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 9/12

-Single AA chain with a long N terminus

Single TMD

Binding _> dimers_> trk-> Stimulated

NT actions at trk receptors

* Ligand binds

* Dimerization

*Phosphorylates each other

-At tyrosine residues

* Protein kinases activated

* Slower acting -> Long term regulation

Trk receptor

- Mediate neurotropic factor actions

- Subtypes

--> trkA= Nerve growth factors

trkB=

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 10/12

trkC=

Intracellular receptor

- Regulate gene expression

Zinc fingers= conserved DNA binding domain

Ligands have to enter cell -Alter gene transcription

-Slow onset

-Long term effects

Drug effects on synaptic transmission

=See slide

Autoreceptors

-Similar to Postsynatpic receptors, but location is different

-Located on the terminal

-Somatodendritic

-Mechanisms = Slow cell firing

-Actions of autoreceptors= Somatoden. -> effects on ion channels

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 11/12

Influence release

-Terminal, but also somatoden.

--> Alter synthesis

--> Influence calcium by changing the influence of calcium channels

Cell can release NT, but then a feedback occurs then on an autoreceptor

These were classical methods=Typical

Non-classical (atypical)

Classic- Anterograde signaling

Endocannabinoids-THC

Non-classical-> hormones

can act extrasynaptically-Membrane bound receptors

Trk receptors and GPCRs

Intracellular responses.

End of A

8/11/2019 Neuro 413 2.18.14

http://slidepdf.com/reader/full/neuro-413-21814 12/12