The basic principles of neuropharmacology Flashcards
Ligand
Any chemical that binds to/combines with a receptor
Receptor
A cellular macromolecule/assembly of macromolecules concerned directly and specifically in chemical signalling between cells
Binding of ligands to receptors 1
Active process, happens due to alignment of 3D shape and biophysical properties (forces) between the ligand and binding site of the receptor
Binding of ligands to receptors 2
Multiple points of interaction may be needed within a binding site for binding to occur
Hydrophobic and hydrophilic charge sites
Van der waal, electrostatic and covalent
Binding of one part of the molecule can facilitate/prevent the binding of another part (e.g through shape change)
Endogenous ligands
Ligands produces naturally by the body e.g neurotransmitters
Exogenous ligands
Endogenous ligands that are synthesised in the lab or modified to change their properties
Specific binding
Calculated as the difference between total and nonspecific binding and reflects the amount of radiogland bound to a specific binding site
Non-specific binding
Represents the nonsaturable portion of binding that is presumably not associated with specific binding under investigation
Total binding
The amount of binding observed
Comprised of 2 components:
1. Specific binding (saturable)
2. Nonspecific binding
Quantification of radioligand binding
When a ligand is at equilibrium with the receptors, it is quantified according to:
1. The affinity of the biding, which is expressed as a dissociation constant (Kd)
2. The amount of binding (Bmax)
Agonists
Evoke (produce) effects in biological tissue
- they can be full, partial of inverse
Antagonists
Do not have effects on their own biological tissue but can block effects evoked by agonists
- thus their effect is to antagonise the action of an agonist
- can be competitive and non-competitive
When plotting quantification of agonist effect, which graph is preferred? Why?
The logarithmic plot is preferred for visualising concentration response relationships as it becomes easier to accurately determine the potency of the ligand
Partial agonist
When it binds to a receptor it elicits only a small response because it lacks a portion of the molecule enquires for the full physiological effect/it binds to a slightly diffferent sight on the receptor
- whilst being less efficacious, they can be more potent than a full agonist
Partial vs. Full agonist
- in the presence of a full agonist a partial agonist will act as a functional agonist, competing with the full agonists for the same receptor
- this reduces the ability of the full agonist to produce its maximal effect
Receptor desensitisation
Repeated application of agonists can lead o receptor tolerance.
- can be overcome by increasing dose
Linear relationship —> maximal response when all receptors are occupied
Hyperbolic relationship
- in most mammalian systems the relationship between occupancy and drug response is hyperbolic
- maximal responses at less than maximal receptor occupancy
Some receptors are ‘spare’
U-shaped curve
Indicates that the biological response is elicited by an agonist progressively increasing as the the agonist concentration increases - subsequently peaks at a moderate concentration
Competitive antagonists
Competes with an agonist or (endogenous ligand) for the same binding site on the receptor.
The agonist does not alter the efficiency of the agonist because the same number of receptors are available to both drugs.
Hence if you increase the concentration of the agonist, it will overcome the effects of a competitive antagonist.
Non-competitive antagonist
Works at a completely different binding site and alters the configuration of the receptor for the agonist. It reduces the number of receptors available for the agonist to bind to.
The potency remains the same but the efficiency is greatly reduced
How do inert antagonists produce a behavioural response?
- preventing agonist action = preventing biological effect
- in the presence of constant concentration of an agonist (endogenous or exogenous) and by systematically changing the agonist concentration we can quantify the inhibitory effect of the antagonistic action on the agonist evoked response
IC50 value
- half maximal inhibitory concentration
- indicated how much antagonist is needed to inhibit a biological response by half
- can be used to compare potencies of antagonists in different tissues
Affinity (Kd)
Describes the strength of the binding between a ligand and its target substrate
Efficiency
Measurement of the maximum biological effect that a drug can produce
Potency
Refers to the amount of ligand requires to achieve or prevent a defined biological effect
Is it possible for a ligand to be potent but also have low efficiency?
Yes
Concept of selectivity
Most ligands have affinity to many receptors
