Lectures 1-6 Flashcards
What four classes of drug targets?
Receptors, ion channels, transporters and enzymes
Give a general definition for a receptor and state its two components
A molecule which binds to a soluble physiogical mediator to have a direct or indirect effect; comprises a ligand binding domain and a tranduction (effector) mechanism
What are the four general categories of receptors?
ligand-gated ion channels, GPCRs, Kinase linked receptors, nuclear receptors
Give a description of function and structure for ligand-gated ion channels
Cause hyperpolarisation or depolarisation as they let ions pass through after a ligand binds. Have a direct effect, with change occurring in miliseconds.
Structure= oligomeric assembly of subunits around a central pore
Give a description of function and structure of GPCRs
Endogenous mediator binds to effector and causes a 2nd messenger effect downstream. Effect is indirect via a G-protein and occurs in seconds.
Structure= monomeric or oligomeric assembly of subunits comprising 7 transmembrane helices with a g-protein coupling domain
Give a description of function and structure of kinase-linked receptors
Binding to the receptor causes activation of a kinase, leading to protein phosphorylation within hours (direct effect)
Structure= Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain
Give a description of function and structure of nuclear receptors
Respond to mediator molecule getting in to the nucleus of the cell and binding to a receptor on the membrane- effects take hours as they are via DNA
Structure= monomeric structure with separate receptor and DNA binding domains
Give a detailed description of the structure of ligand gated ion channels
Protein has a C-terminal domain, an N-terminal domain and four transmembrane domains; 2nd transmembrane domain lines the channel pore
What is the specific structure of the glutamate activated ion channels?
3 transmembrane domains with 2TM domain a re-entrant loop that doesn’t go the whole way through the membrane but forms the pore.
How is the structure of the cys-loop family different in terms of the structure of subunits present? How does this compare to the structure of I glutamate subunits?
Subunits have a pentameric structure formed of 5 proteins, which can all be heteromeric. Two cysteines present in the N-terminal domain form a disulphide bridge
I glutamate subunits have a tetramer (4 protein) structure
Describe the general properties of ionotropic receptors and give examples of molecules that interact with these recetors
Generally, fast neurotransmitters act here. GABA can bind to the GABA-A receptor, acetylcholine can bind to the NAChR and glutamate can bind at NMPA/AMPA receptors.
4-5 protein subunits assembled around a central pore (can be heteromeric or homomeric) and in the absence of the NT, the pore is closed.
What are the different gaba subunits responsible for?
a1 = sedation, a2/3 = anxiety, a5= cognition
What is the purpose of using flumazenil as a control in diazepam studied?
Has high binding affinity to GABA receptors but no efficacy
Define the term agonist
A drug that binds to and activates a receptor
Define the term allosteric modulator
A drug that binds to a receptor at a site different to the active site. Induces a conformational change in the receptor, which alters the affinity for the receptor for the endogenous ligand
Define the term antagonist
A drug that attenuates the effect of an agonist. Can be competitive or non-competitive, reversible or irreversible
Define the term Bmax
Maximum amount of a drug/radioligand in pM that can bind to receptors in a membrane preparation
For what purpose is the Cheng-Pursoff eqn used?
Used to determine a Ki value from an IC50 value measured in a competition radioligand binding assay
