Wk4 Drug Agonists And Antagonists Of Pharmacology Flashcards
What is the first problem of receptor signalling
The problem is to form some picture of cell structure that will explain the fact that a few thousand of these molecules when they unite with the cell suffice to modify its functions.
Ways of regulating cell function
altered membrane potential
altered enzyme activity
altered gene expression
Most drugs affect cell function via (physiological) receptors
They act “hormone‐like” = an artificially made hormone molecule may directly be used as a drug
e.g. glucocorticosteroids or tyroxine
Receptors and the effects of drugs
How drugs produce effects by binding to receptors
‐ various ways in which effects are produced ‐ agonism How drugs block effects by binding to receptors
‐ ways in which effects blocked or reduced –
antagonism and desensitization
Allosteric effects on receptors
The GABAA receptor
(gamma‐amino‐butyric acid)
• ligand‐gated chloride ion channel in the brain
• benzodiazepine agonists bind to GABAARs
and increase the affinity of the GABA binding site for GABA, thereby increasing channel opening
Benzodiazepine receptor ligands
Agonists – diazepam, lorazepam
Antagonists – flumazenil (“antidote”)
Inverse agonists – beta‐carbolines
Glutamate-gated chloride receptors
common channels in the nervous system
important target for anti‐parasitic drugs e.g. ivermectin
“Spare receptors”
Some highly efficacious agonists (super‐agonists) can produce a maximal
response from the cell without binding to all of the available receptors
For example, goserelin (Zoladex) is a super‐agonist of the gonadotropin‐releasing hormone receptor (GnRH‐R). It suppresses production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer.
Partial agonists
Low efficacy, partial agonists cannot produce the cell’s maximal response, even when they have bound to all of the available receptors.
1 example for partial agonists at particular receptors: buprenorphine is an opioid used to treat opioid addiction, moderate acute pain and moderate chronic pain
Competitive antagonists
atropine (from the deadly nightshade) at muscarinic receptors propranolol at beta‐adrenoreceptors
sildenafil at phospho‐diesterase 5 (PDE5) competing with cGMP
• bind reversibly, at the same site as the (natural) agonist
• produce parallel shift to the right of agonist dose/response curves
Irreversible antagonists
phenoxybenzamine at alpha‐adrenoreceptors
second/third generation proteasome inhibitors (based on bortezomib)
– bind irreversibly, at the same site as the agonist, forming a covalent bond or binding incredibly tight
– decrease the maximal response to agonists
•may produce an initial shift to the right of the dose/response curve with no decrease in max
•evidence for spare receptors
Types of antagonism
Competitive antagonists
Irreversible antagonists
Allosteric antagonists
Channel blockers
“Physiological antagonists”
Allosteric antagonists (rare)
gallamine at the muscarinic receptor beta‐carbolines at the GABAA receptor —> allosteric (enzyme) inhibition
‐ bind (reversibly) at a distinct site from the agonist and decrease agonist affinity
‐ reduce likelihood of agonist binding
Channel blockers
phencyclidine at the NMDA receptor
–bind inside the channel (“plug”) and prevent the passage of ions
–binding of channel blockers tends to be enhanced by receptor activation
•use dependence
Physiological antagonists
They antagonise the physiological effect of some agonists, but via different mechanism
1) several substances that have anti‐histaminergic action despite not being ligands for the histamine receptor: epinephrine and other such substances are physiological antagonists to histamine
2) endocrine disruptors; some of the inhibit conjugation reactions
Desensitization
Prolonged or repeated exposure to an agonist reduces the response to that drug
Tolerance to heroin
‐ increased adenylyl cyclase activity in the brain
Inactivation of nicotinic receptors
‐ receptor driven into an inactivated state
This may come by through up‐regulation of the receptor for the respective drug… among other mechanisms.
alcohol dehydrogenase is upregulated so if you have often exposure to alcohol your liver will grow with the challenge
Receptor classification
Receptors are classified on the basis of the selective action of drugs
They are named according to the transmitter or hormone with which they interact – e.g. acetylcholine receptors
Most hormones interact with more than one type of receptor
– (subtle) differences in protein structure underlie differences between subtypes
Experimental proof that transmitters may act on more than one receptor
This is experimental proof of two different classes of acetylcholine (ACh) receptors: “muscarinic” and “nicotinic” ones.
Only after the high‐affinity muscarinic ones have been poisoned, the low‐affinity nicotinic ACh receptors become visible.
Receptor super-families
Integral ion channels eg nicotinic receptor glycine receptor
Integral tyrosine kinases eg insulin receptor
Steroid receptors = nuclear receptors e.g. estrogen receptor, androgen receptor
G protein coupled receptors eg muscarinic rec. adrenoreceptors
Cytokine receptors e.g. prolactin receptor, EPO receptor growth hormone
TNF receptor
Some more words on nuclear receptors
DBD = DNA‐binding domain LBD = ligand‐binding domain RE = response element
Nuclear receptors
- ACT in the nucleus, but are most often - located in the cytoplasm
Their ligand-binding domain functions like a folding sensor - without steroid ligand, it is unfolded - with steroid it gets folded.
The DNA-binding domain mediates binding of nuclear receptors to thousands of sites within the genome.
