MSK 05: Opioids Flashcards
Describe the structure and function of opioid receptors and describe how opioid drugs interact with these receptors.
- GPCR
- secondary signaling
- padlock model
OR Signaling
- agonist binding induces conformational change in cytoplasmic regions of receptor which activates coupled G-proteins
- 𝛼-monomer and 𝛽𝛾-heterodimer conduct secondary messaging effects
- 𝛼-monomer inhibits adenyl cyclase, which blocks cAMP formation and modifying signaling pathways that lead to changes in gene expression
- 𝛽𝛾-heterodimer interacts with voltage dependent Ca2+ channels to block Ca2+ import, which reduces presynaptic neurotransmitter release
- 𝛼-monomer and 𝛽𝛾-heterodimer can open K+ channels, releasing K+ out of cell
- blockage of Ca2+ channel and opening of K+ hyperpolarize the neuron, making it more difficult to fire
µ-Opioid Receptor (MOR or µOR)
- locations: brain, spinal cord, sensory neurons, intestinal tract
- agonists: morphine, heroin, methadone, codeine, oxycodone, etc.
- antagonists: naloxone, naltrexone, and others
- 3 subtypes (µ1, µ2, µ3) – ligands tend to be non-selective for different subtypes
- agonism µOR results in: analgesia, physical dependence, reduced GI motility (constipation), respiratory depression, euphoria, miosis
ĸ-Opioid Receptor
- 3 subtypes (ĸ1, ĸ2, ĸ3)
- locations: brain, spinal cord, sensory neurons
- agonists: ketazocine, meperidine, butorphanol, nalbuphine, codeine, hydromorphone, morphine, etc.
- antagonists: buprenorphine, dezocine, and others
- agonism results in: analgesia, anticonvulsant, depression, dysphoria
δ-Opioid Receptor
- 2 subtypes (δ1, δ2)
- locations: brain, sensory neurons
- agonists: desmethylclozapine, norbuprenorphine, cannabidiol, tetrahydrocannabinol, xorphanol
- antagonists: buprenorphine, naltriben, naltrindole
- agonism results in: analgesia, antidepressant, convulsions, physical dependence, respiratory depression
ζ-Opioid Receptor
- opioid growth factor receptor
- locations: brain, heart, liver, muscles, kidney, pancreas
- agonists: Met-Enk
- agonism results in: tissue growth, cancer cell proliferation
Full Agonists
- strong analgesics
- have activity equivalent to morphine but may differ in their potency to activate opioid receptors (ie. effective at lower or higher doses)
- most are primarily μ opioid receptor agonists, with weaker ĸ activity, and little to no δ activity
- ie. hydromorphone, fentanyl, meperidine, methadone
Partial Agonists
- moderate or weak analgesics
- exert less analgesia, regardless of dose, than morphone
- ie. oxocodone (moderate), codeine (weak)
Agonist/ Antagonist (Mixed)
- weak analgesics
- buprenorphine: partial agonist at μ, weak antagonist at δ and ĸ
- pentazocine, nalbuphine and butorphanol: ĸ receptor agonists (dysphoria) with partial or no agonist effect at μ receptor
Atypical
- weak analgesics
- designed to bind multiple targets related to analgesia
- tramadol: serotonin and noradrenaline reuptake inhibition + weak μ receptor agonist
- tapentadol: noradrenaline reuptake inhibitor + weak μ receptor agonist
Recognize key features of endogenous opioids (enkephalins) and identify how their structural features mimic opioid drugs (ie. morphine).
- tyrosine mimicry (except fentanyl)
- 5 key features
What are the 5 key features of OR ligands?
- scaffold to place functional groups in appropriate orientation
- phenol group: hydrogen bond donor
- phenol group: Pi-stacking
- ionic interaction: positively charged nitrogen at physiologic pH
- hydrophobic interaction (agonist vs. antagonist)
Describe enkephalins.
quickly metabolized and CANNOT be used therapeutically
What does modifying tyrosine phenol (ie. codeine) do?
impairs activity of opioid analgesics, but not complete loss of activity
- fentanyl lacks phenol group
What does morphine mimic?
morphine scaffold mimics naturally occurring enkephalins
Describe the key features of opioid drugs and relate their structures to the nature of their activity (ie. agonist vs. antagonist).
- key ring features leading to increased potency
- N-allyl and methylcyclopropyl group = OR antagonist
- increased activity of phenethyl morphine analogues
- heroin is prodrug with two active metabolites
SAR studies with morphine scaffold have identified key parts:
- Ring A: phenol is generally required – exceptions are fentanyl and carfentanil
- Ring B, C and D: expendable, but geometry is important
- Ring E: absolutely required, but can be replaced with piperidine (ie. in fentanyl)
