Research led seminar 1 Flashcards
Actions and adverse eects of opioids
There are 3 types of opioid receptor, but every single one of those eects is mediated by morphine preferring opioid receptor. So, the good stu (pain relief) and the bad stu (nausea, respiratory depression, tolerance, addiction etc.) are all through one receptor
GPCRs
G protein-coupled receptors
Opioid receptors are a subset of GPCRs specifically involved in mediating the effects of opioids.
Types of Opioid Receptors:
There are three main types of opioid receptors, all of which are GPCRs:
Mu (μ) Receptors: Primarily responsible for the analgesic (pain-relieving) effects of opioids, as well as euphoria, respiratory depression, and physical dependence.
Delta (δ) Receptors: Involved in analgesia and mood regulation.
Kappa (κ) Receptors: Associated with analgesia, dysphoria, and psychotomimetic effects.
Mechanism of Action:
It produces a strong G protein signal, inhibiting nerve cell function.
Binding: When an opioid (such as morphine, heroin, or endogenous opioids like endorphins) binds to the opioid receptor, it induces a conformational change in the receptor.
G Protein Activation: This conformational change activates the associated G protein (often a Gi/o type).
Gi/o Protein: The Gi/o protein inhibits adenylate cyclase, reducing the levels of cyclic AMP (cAMP) within the cell.
==> Decreased cAMP results in reduced cellular excitability and various downstream effects.
Beta and Gamma Subunits: These subunits can open potassium channels (leading to hyperpolarization) and close calcium channels (reducing neurotransmitter release).
==> hyperpolarization, making it harder for neurons to fire action potentials.
=> Closing of calcium channels reduces neurotransmitter release at synapses, contributing to analgesic and sedative effects.
Q: Where are opioid receptors located in the body?
A: They are located not only in pain-sensing areas but also in respiratory networks and reward systems in the brain.
Q: What happens to opioid receptors after a few days of exposure to opioids?
A: Tolerance builds up as the receptor’s interaction with G proteins becomes weaker.
Q: Why might partial agonists be beneficial in some cases?
A: Partial agonists can provide the desired effects with potentially fewer adverse effects.
Q: What is a key safety concern with morphine use?
A: Morphine can produce significant effects even with partial receptor occupancy, leading to potential overdose and death.
Q: How can low G-protein efficacy improve the safety of opioids?
A: Low G-protein efficacy reduces the maximal response, which can lower the risk of severe side effects like respiratory depression.
A: Buprenorphine is a partial agonist with lower intrinsic efficacy, reducing the risk of respiratory depression and overdose.
=> A: It is used as a replacement therapy for heroin and methadone.
Q: What does the term “spare receptors” refer to?
A: It refers to the concept that not all receptors need to be occupied by an agonist to produce a maximal response.
Q: How does opioid efficacy affect safety?
A: Opioid efficacy affects safety because higher efficacy can lead to stronger effects, which may increase the risk of adverse effects such as respiratory depression. Reduced recruitment of regulatory proteins like arrestins can also alter the safety profile of opioids.
Q: What is the role of arrestins in opioid receptor signaling?
A: Arrestins help regulate GPCR signaling by desensitizing the receptor, preventing overactivation, and promoting receptor internalization. This can reduce the adverse effects of opioids and improve their safety.
Question: What are the stages in drug development using Glycine Transport Inhibitors as an example?
Answer:
Discovery: Identifying a target (GlyT2) and potential inhibitors.
Synthesis and Testing: Creating and testing new lipid compounds for potency (IC50) and stability.
Optimization: Modifying compounds (head/tail groups) to improve potency and reduce metabolism.
Specificity Testing: Screening for off-target effects (other neurotransmitter transporters, ion channels, receptors).
Pharmacokinetics: Ensuring the drug can cross the blood-brain barrier and accumulates in the brain.
In vivo Testing: Testing efficacy and side effects in animal models.
Human Trials: Conducting clinical trials to evaluate safety and efficacy in humans.
Question: How can site-directed mutagenesis and molecular modelling be used to design drugs?
Answer:
Site-Directed Mutagenesis: Introduces specific mutations to study the effects on drug binding and function. Helps confirm binding sites and mechanism of action.
Molecular Modelling: Uses computer simulations to predict how drugs interact with their target. Guides the design of more potent and selective drugs by visualizing interactions at the molecular level.
Question: How can AI be used in drug discovery?
Answer:
Screening: AI can screen billions of compounds to identify those that are likely to bind to a target (e.g., GlyT2).
Optimization: AI helps optimize compounds by predicting their pharmacokinetic and pharmacodynamic properties.
Efficiency: Speeds up the drug discovery process by prioritizing the most promising compounds for further testing.
Question: What features of lipids are important for the inhibition of glycine transport?
Answer:
Head Group: Influences binding affinity and specificity.
Tail Group: Affects the compound’s stability and interaction with the transporter.
Double Bonds: Presence of double bonds can affect oxidation and stability.
Question: Identify parts of the lipids that form hydrophobic interactions, ionic interactions, and π-cation bonds.
Answer:
Hydrophobic Interactions: Formed by the lipid tail with amino acids like F567, M570, I520, L436, V523, L557.
Ionic Interactions: Formed by charged groups in the head with oppositely charged residues on GlyT2.
π-Cation Bonds: Formed by aromatic rings in the head group with cationic residues like W563, Y550.
