1- Drug-Receptor Interactions Flashcards
What are drug receptors?
they’re macromolecules that, upon binding to a drug, mediate those biochemical and physiologic changes
What is that binding site of the drug?
The site on the receptor at which the drug binds
How is a drug receptor selective for a certain drug?
The 3-D structure, shape and reactivity of the site, and the inherent shape, structure and reactivity of the drug.
What is the affinity for a receptor?
It is the result of chemical interactions between the two molecules and the favorability of this interaction
What are covalent interactions?
They are very strong interactions between the drug and the receptor that they are essentially irreversible
What must the cell do if a drug binds to a receptor covalently forming an interactive complex?
It must synthesize a new receptor molecule to replace the inactivated protein
How strong is ionic bonding?
Stronger than hydrogen bonds but weaker than covalent bonds
What is Van der Waal forces?
They provide weak attractive forces for drugs and their receptors
Is the interaction between a drug and a receptor the formation of only one type of bond?
No. Rarely is a drug receptor binding caused by a single type of interaction. Essentially multiple week forces comprise the majority of the drug receptor interactions
What is the 2 important reasons why enatiomers are important for drug receptor interactions?
Usually one form is a lot stronger than the other form, and sometimes one form is therapeutic and one form is toxic.
What is induced fit?
It’s when the binding of a drug to its receptor results in a change in confirmation of the receptor for better binding of the drug.
What is a good example of induced fit using an exogenous drug?
Exogenous insulin stimulates the insulin receptors to the same extent despite differences in amino acid sequences
Besides a tighter binding of the receptor to the drug induced fit, what other outcome might result?
Binding of the drug might make the receptor more or less functional than normal.
How might drug and receptor structures confer specificity on the interactions between drugs and their receptors?
Structure of the receptor determines where the protein is located in relationship to the cellular boundaries such as the plasma membrane
How can hydrophilic drugs passed through the Plasma membrane to get to cytoplasmic receptors?
Transmembrane channels
How can lipophilic drugs get to their intracellular targets?
Since they are fat-soluble they just pass right through the membrane.
What is the relationship between the Restriction of the receptor and side effects?
The more the restricted the receptor is, the more selective the drug is for the receptor and therefore fewer side effects
What is an example of a drug that is not very specific and therefore creates large side effects?
Drugs that have a general function such as DNA synthesis are likely to cause significant toxic side effects, Like chemotherapeutics for the treatment of cancer
Is a drug more or less selective if the receptor – defector coupling mechanisms differ among various cell types?
More selective
What is a partial agonist?
It’s a drug that produces a submaximal response upon binding to their targets
What is a competitive antagonist?
They are drugs that directly blocked the binding site of a physiologic agonist
What is an inverse agonist?
They’re drugs and that cause constitutively active targets to become inactive
What are noncompetitive antagonists?
They are drugs that bind to sites other than where the physiologic agonist binds and thereby prevents the confirmational change required for receptor activation
What are ligand gated channels?
They are channels that the conductance is controlled by a ligand binding to the channel
What are voltage gated channels?
They are channels in which conductance is regulated by changes in voltage across the membrane
What are second messenger regulated channels?
Their channels in which conductance is controlled by ligand binding to plasma membrane receptors that are links to the channel in someway
What is a very important ligand gated channel on muscle cells?
Nicotinic acetylcholine receptor
What is the mechanism of local anesthetics?
They block voltage gated sodium channels
What is the mechanism of action of benzodiazepines?
They inhibit neurotransmission by GABA to increase the conductance of chlorine ions across neuron membranes
What is the most abundant class of receptors in human body?
G protein coupled receptors
What is the fxn of the α subunit of the G-protein?
Exchange GDP for GTP and activating effectors
Give the pathway of activations that occurs during α subunit binding to AC in Gs receptors
Ligand binds –> α subunit diffuses with GTP to adenylyl cyclase (AC) –> AC converts ATP to cAMP –> cAMP activates PKA –> protein phosphorylation
Give the pathway of activations that occurs during α subunit binding to PLC in Gq receptors
Ligand binds –> α subunit with GTP binds to PLC –> IP3 and DAG made –> DAG activates PKC –> protein phosphorylation
Generally, what is activated with Gs proteins?
Ca++ channels, Adenylyl cyclase
Generally, what is activated with Gi proteins?
K+ channels, inhibits AC
Generally, what is inhibits with Go proteins?
Ca++ channels
Generally, what is activated with Gq proteins?
PLC
Where are β1 receptors located?
Heart (SA node and myocardium), adipose tissue
What are the effects of β1 activation?
increased HR, contractility of heart, lipolysis
Where are the β2 receptors located?
Bronchial smooth muscle, GI, uterus, bladder, liver, and pancreas
What are the effects of β2 activation?
Dilation of bronchioles, relaxation of gut, relaxes bladder and uterus, increases gluconeogenesis in liver, stimulates insulin release from pancreas
What are the functions of transmembrane receptors with a cytoplasmic enzymatic domain?
transduce and extracellular ligand-binding interaction into an intracellular action through the activation of a linked enzymatic domain
What are the main signals that bind to tyrosine kinase receptors?
Hormones and growth factors.
What is the main mechanisms of how tyrosine kinase receptors work?
phosphorylation of tyrosine residues on the cytoplasmic tail of the receptor, leading to phosphorylation of a number of cytosolic signaling molecules
Since tyrosine kinase receptors play a key role in cell growth/differentiation, mutations could cause what problems?
mutations in these receptors can lead to cancer and uncontrolled cell growth
What types of enzymes remove phosphate groups from specific tyrosine residues?
tyrosine phosphatases
What type of transmembrane receptors with a cytoplasmic enzymatic domain does TGF-β superfamily use?
Receptor serine/threonine kinases
What is required for a ligand to bind to intracellular receptors?
It has to be lipid soluble to cross the plasma membrane
Which lipophilic anticoagulant works by binding to enzymes in the cytosol (a type of intracellular R)?
warfarin
Steroid hormones typically bind to intracellular receptors in which part of the cell?
Nucleus (they act as transcription factors)
Extracellular enzymes have binding sites for drugs where in the body?
Basically anywhere outside the plasma membrane
Give an example of an extracellular receptors that is used to lower blood pressure.
ACE Inhibitor drugs lower blood pressure. Angiotensin converting enzyme (ACE) converts angiotensin I –> angiotensin II (vasoconstrictor)
Why can many different drugs produce the same effects via second messengers?
Because 2nd messengers provide cells with a set of common points upon which numerous outside stimuli could converge to generate a coordinated cellular effect
What is signal integration?
When ligands bind to receptors that have opposite 2nd messenger effects, like activation of Gs receptors (which activates AC) and Gi receptors (which inhibits AC)
What is homologous desensitization?
the effects of agonists at only one type of receptor are diminished
What is heterologous desensitization?
the effects of agonists at two or more types of receptors are coordinately diminished
What typically causes heterologous desensitization?
Caused by drug induced alteration in a common point of convergence in the mechanisms of action of the involved receptors, such as a shared effector molecule
What is receptor inactivation?
completely turning off the receptor to stimulation by ligand.
How does a receptor get inactivated?
Results from phosphorylation of the receptor
What is the refractory of the receptor?
it’s the state following activation in which the receptor requires time before it can be stimulated again
What is down-regulation of the receptor?
a molecular mechanism in which the receptor NUMBER can be altered
What is the general mechanism of receptor down-regulation?
prolonged receptor stimulation by ligand induces the cell to endocytose and sequester receptors in endocytotic vesicles. Once the stimulus that caused the down-regulation is gone the receptors can be recycled back up to the cell surface to be used again
What are 2 classes of drugs that lack receptors?
osmotic diuretics and antacids
What is mannitol?
Osmotic diuretic
What is the mechanism of action of mannitol?
Secreted into the lumen of the nephron and increases the osmolarity of the urine to such a degree that water is drawn from the peritubular blood into the lumen.
What is the mechanism of action of antacids?
Act nonspecifically by absorbing or chemically neutralizing stomach acid
