chem e-120 harvard university extension school 1 pain sar of opioids april 13, 2011
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CHEM E-120Harvard University Extension School
1
PainSAR of OpioidsApril 13, 2011
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Pain
Nociceptive Pain
due to a stimulus (hammer, campfire) activation of high threshold sensory pathwaysacting via neurons called nociceptors
Clinical Pain
Inflammatoryvariety of chemical mediators stimulate nociceptors e.g. cytokines (IL-1 and TNF-α)
Neuropathicinitiated or caused by a lesion or dysfunction of the sensory nervous systemFibromyalgiachronic, widespread pain, fatigue, and heightened pain in response to pressure (allodynia)
2
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Neuronal Pain Pathway
Dorsal Horn
3
Drug Targets/Mediators
Ascending PathwayNMDA/glutamateSubstance P/NK-1Nitric oxide
Descending PathwaySerotoninGABANorepinephrineOpioids
Peripheral TissueNSAIDSProstaglandinsHistamines
sensation of pain
amygdala, NAccdysphoriaunpleasant aspectsof pain
flexor response
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Nerve Fibers and Nociceptors
Nerve fiber types organized for size (axonal diameter) of 1 - 4. 1 -3 are myelinated and Group 4 are demyelinated. Also classified as A, B, or C where C is demyelinated.
Larger diameter fibers conduct signal faster that smaller diameter fibers.
Group 3 – nocicpetion (sharp pain), cold receptors, 5 – 30 m/secGroup 4 – nociception (dull pain), warmth, itch, 0.5 – 2 m/sec
Transient Receptor Potential (TRP) – nonselective tetrameric ion channels that respond to heat and cold. TRPV1-4, TRPM8, TRPA1
TRPV1 - Threshold of > 430C (capsaicin, H+, anandamide)TRpM8 – Threshold of < 250C (menthol)
Mechanical nociceptors
4
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Role of Ion Channels in Pain
5
Action potential from site of stimulus to cortex mediated by Na+, K+, and Ca2+
voltage-gated ion channels.
Na+ mediates action potential
Opening of Na+ channels propagates action potential by depolarization of neuron Nav 1.3 is a potential target, is upregulated following injury.
K+ mediates membrane potential
Opening of channel allows K+ flow out polarizing the neuron. GIRK – G-protein-coupled, inward rectifying potassium channel. Activated by opioids, cannabinoids, and α-2 adrenergic agonists
Ca2+ mediates neurotransmitter releasePresynaptic activation releases neuropeptides (substance P) and glutamateCav 2.2 inhibitor - Ziconotide
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Pain Receptors – Dorsal Horn
6
Glu mediates fast transmission
G-protein-coupled, inward rectifying potassium channel
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Dorsal Horn Neuronal Networks – Sites for Analgesics
7
sites of action to control pain
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Sensitization
8
Normal nociceptive pain perception follows well regulated pathways and ceases onremoval of noxious stimulus.
Neuropathic pain is characterized by exaggerated pain that continues in the absence of a noxious stimulus.
Peripheral Sensitization
Increased sensitivity ofNociceptors to stimulus
Conformational changes in GPCR2nd messenger system activationactivation of arachidonic acid cascade
Central Sensitization
Increased activation of dorsal hornneurons and transcriptional changesUpregulation of transcription factorsIncrease COX and NOS synthesis
Windup phenomenon
Repeated stimulation of C fibersResponse to stimulus increases postsynaptic NMDA and NK1 activation (medication- block NMDA receptors)
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Sensitization
9
transcriptional changes
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10
Sensitization of Peripheral Nociceptors
Kandel Chapter 24
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General Anesthetics
11
State of drug-induced absence of perception of all sensations: inculdes unconciousness, analgesia, amnesia, and muscle relaxation.
General anesthesia is usually induced with intravenous anesthetics, and maintained with inhalation anesthetics
First demonstrated at MGH in 1846 – diethyl ether
Inhalation anesthetics:• Very diverse drugs: ether, nitrous oxide, halothane• Mechanism of action largely unknown (probably inhibition of glutamate receptors and
increased activity of GABA receptors)• Actions are affected by cardiac output and ventilation rate• Elimination predominantly through exhalation of the unchanged gas
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General Anesthetics
12
Intravenous anesthetics:• Thiopental
Barbiturate with very high lipid solubility, rapid action, but accumulates in fat with extended use, narrow therapeutic range, no analgesic effect
• PropofolRapidly metabolized => quick recovery, drug of choice for out-patient surgeryUsed as continuous infusion
• KetaminePhencyclidine analogue, good analgesia and amnesia, High incidence of hallucinations during recovery.
• Midazolame (Benzodiazepine)
OH
Propofol
OH
BHTpreservative
N
PhencyclidenePCP, angel dust
NH
O
Cl
Ketamine
PCP mimics both negative and positive symptoms of schizophreniaNMDA (glutamate) antagonist. Binds to open ion channel, blocks glutamate transmission
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General Anesthetics
13
Potency and speed of induction/recovery depend on two properties of the anesthetic:
• Solubility in blood (blood:gas partition coefficient) Speed of onset is inversely correlated with the solubility in blood (more soluble =>
slower onset): blood acts as a reservoir that “needs to be filled”• Solubility in lipid (oil:gas partition coefficient)
Determines the potency of the anesthetic More lipophilic anesthetics have higher potencyLipophilic anesthetics gradually accumulate in body fat (> prolonged “hang-over”)
Modern anesthesia:Employs a combination of drugs to achieve the goals of a “balanced anesthesia”:
– Anxiolytic premedication (Diazepines)– Autonomic stabilization (Atropin: prevents visceral reflexes)– Analgetics (Opioids: Fentanyl)– Muscle relaxant (Pancuronium)
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Penetrate membrane in unionized (neutral) form
pKa clogP % base at pH 7.4 onset (minutes)
Lidocaine 7.9 1.95 25% 2 – 4
Procaine 9.1 2.5 2% 14 - 18
Bind to Na+ channel in theionized form
General Anesthetics
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Local Anesthetics/Analgesics
15
Cocaine First local anesthetic, Isolated in 1860 from Coca (Indians, who chewed Coca leaves for their
psychotropic effects, knew about the numbing effect they produced on the mouth and tongue)
Procaine (First synthetic local anesthetic)
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
Act by inhibiting CycloOXygenases (COX) => no PG production (PG sensitize nocireceptors)COX-1: Constitutively expressed => house-keeping functionCOX-2: Induced by pro-inflammatory factors (TNFα, IL-1)COX-3: Just recently discovered
Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is reversible,with the exception of Aspirin) => housekeeping PGs reduced => side effects (gastrointestinal, bronchospasms,…)
2nd generation NSAIDs:
COX-2 specific => only the inflammatory response is inhibited => fewer side effects
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Analgesics
16
COX-2 specific NSAIDs:
• Rofecoxib (Vioxx®)Launched in 1999Marketed in 86 countries: 2.5 bill.$ /yearRecent trial to test Rofecoxib for efficacy in colorectal polyps treatment revealed
an increased risk of heart disease (+ 50%) after 18 month continuous use
Sept. 2004: Merck voluntarily withdrew Vioxx® from the market
• Celecoxib (Celebrex®) April 2005: FDA required Pfizer to include a “boxed warning” indicating apotential risk of cardiovascular side effects
• Valdecoxib (Bextra®)April 2005: FDA required Pfizer to withdraw Bextra® from the market due tounfavorable risk vs. benefit profile (mostly already known adverse skin reactions)
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Opioid Analgesics
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For moderate to severe pain the drugs of choice are based on the opioid analgesics acting as agonists on opioid receptors.
Alkaloids derives from Papaver somniferum– Already used 4000 B.C. (opius greek: “little juice”)– 1805: Morphine isolated (morpheus: Greek god of dreams)– 1874: synthesis of heroin (introduced in 1898 by Bayer as a cough medicine)– Opium tincture heavily used during civil war– Opiates freely available in the US until 1914 (Harrison Act)
MorphineCodeine: 3-methoxy-morphine (CYP2D6 inhibitors (e.g. Fluoxetine) reduce efficacy)Hydrocodone (Vicodin®):– Often combined with NSAIDs– Contained in over 200 preparations in the USOxycodone (OxyContin®)Meperidine (Pethidine): much shorter duration than morphine, used during labourFentanylEtorphine: 1000x more potent than morphine
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Opioid Analgesics
1. Naturally occurring opioids 2. Synthetic analgesics based on morphine
3. Synthetic Analgesics
MorphineButorphanol
Fentanyl
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Opioid Receptors
19
Membrane bound G-protein coupled receptors: Mu, Delta, Kappa
Opioid receptors have generally high homology73 – 76% in TM domains34 - 40% in extracellular domains63 – 66 % in intracellular domains
Mu receptor - 400 amino acids
Endogenous peptidic ligands for opioid receptors, proopioid proteins synthesized in nucleus and transported to synapse via microtubules where they are processed by peptidases
Mu endomorphine-1 (Tyr-Pro-Trp-Phe-NH2) endomorphine-2 (Tyr-Pro-Phe-Phe-NH2) β-endorphin (31 AA)
Delta enkephalins (5 – 8 AA)
Kappa dynorphins (8 – 17 AA)
NH2-Try-Gly-Gly-Phe-
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Opioid Receptor Topology
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% homology (identical amino acids) between the 3 opioid receptors
N-terminus
C-terminus
Extracellular loops 1-3recognition point for endogenous peptides
Intracellular loops 1-3
TM 3,6,7 form binding pocket
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Opioid Mechanism of Action
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Local enkephalin-containing interneurons (ENK) exert both presynaptic and postsynaptic inhibitory actions at the synapses. Opioids decrease Ca2+ influx and increase Serotonergic and noradrenergic neurons in the brain stem activate the local opioid interneurons and also suppress the activity of spinothalamic projection neurons.
NE/5-HT brain
ENKENK
stimulus
To brain
Release of peptidic opioidsopioid receptors pre/post synaptic
Antidepressants as AnalgesicsCNS Drugs 2008,22, 139-156
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Binding Affinity and Efficacy
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Binding affinity
CHO cells mu ([3H]-DAMGO), delta ([3H]-naltrindole or DPDPE), kappa ([3H]-U69593HEK-293 cells
Mouse vas deferens mu, delta, kappaGuinea-pig myenteric plexus-longitudinal muscle mu and kappaRabbit vas deferens kappaHamster vas deferens delta
Functional assays
[35S]GTPγS in CHO, HEK-293 cell membrane preparations
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Animal Models of Analgesic Activity
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Hot-Plate Test – Acute Pain
Animals are injected with test compounds or vehicle (controls) and then placed on the hot plate (550C) one at a time. Latency to respond to the heat stimulus is measured by the amount of time it takes for the animal to lick one of its paws.
Tail-Flick Test – Acute Pain
high-intensity thermal stimulus is directed to the tail of a mouse or a rat. The time from onset of stimulation to a rapid flick/withdrawal of the tail from heat source is recorded.
Formalin Test
states of persistent pain in which tissue damage occurs
Current Protocols in Neuroscience (1999) 8.9.1-8.9.15
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Analgesic Activity
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Opioid Analgesic Dosing
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Neurobiology of Addiction p124
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Binding Model of Morphine
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Asp147 of TM3
His297 of TM6
at pH = 7 1 10
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Morphine SAR Results
27
morphine MOR Ki = 1 nMcodeine MOR Ki = 135 nM
An Introduction to Medicinal ChemistryG. Patrick, 2005, Chapter 21
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Morphine SAR Results
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Morphine SAR Results
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μ/δ/κ (nM)
1.7/85/16
1.1/140/47
charged N+ does not cross BBB but – full analgesic activity icv
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Morphine SAR Results
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Morphine SAR – N Group
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Morphine SAR Results – Analgesic Activity
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Removal of OH reduces activityMethylation reduces activityAcetylation reduces activity
Removal increasesactivity
Removal of OH increases activityOH to ketone reduces activityOH to ketone + reduction of 7,8double bond INC activityAcetylation INC activity
Reduction INC activity
H to OH INC activity
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Structural Changes
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Structural Changes
34
Complete loss of activity
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Structural Changes – Benzomorphans (-C&D)
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Structural Changes - Removal Rings B, C, &D
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Remifentanil: Short-acting analgesic
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N
N
O
Fentanyl
80 X morphine
N
O
O
O
OO
Remifentanil
N
O
O
S
Sufentanil
600 - 800 X morphine
N
O
O
O
OHO
1000 x lesspotent in GPL
350 X les potent in FTW
N
O
O
O
OO
blood
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JMC 1991, 34, 2202
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Structural Changes - Removal Rings B, C, D, & E
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Methadone greater oral potency and longer duration of activity than many other opioids20 mg/8-12 hours. t1/2 ~ 19 hours at pH 5.2, at pH 7.8 t1/2 ~ 42 hours
Propoxyphene (Darvon)Oral dosage ~ 1/12 potency of morphineAnalgesic effect ~ same as aspirin
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Oripavines
40
Etorphine
10,000 X morphineCrosses BBB 300 X morphine20 X mu affinity
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Oripavines
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No analgesic activity
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Buprenorphine
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R Tail-flick (agonist) antagonism
Me 0.005 317
Et 6.8 68
Pr 213 0.17
t-Bu 19 4
Bu 53 0.56
Morphine 1 <0.01
Nalorphine 0.30 1
Mu partial agonistDelta antagonistKappa partial agonist
Analgesic effect w/o toleranceand less respiratory depressionNon-oral (sublingual, transdermal)Suboxone, Subutex®
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Agonist vs Antagonist
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Agonist vs Antagonist
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Overlaps with morphineAgonist activity
antagonistaxial hydroxyphenylbut N-substituentimportant
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Agonist vs Antagonist
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Morphine (gray)
axial 3-methyl restoresantagonist activity
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Agonist vs Antagonist
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Anionic site
Phenolic site
N-substituent site
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Receptor Modeling
47
3D xray rhodopsin (Protein Data Bank)
Alignment of conserved mu amino acid sequences with rhodopsin
ModellerHomology Model
Protonated ligands Stable conformation
Docked by ASP (3.32) + NH+
Interaction and HB phenol &HIS H6.52
Simulatd annealing
The Open Structural Biology Journal, 2008, 2, 8-20
The Modeller, Clustal W, SeqFold and Profile-3D (Verify-3D method) programs were used within the InsightII software platform (Accelrys Inc., v.2000.1).
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Agonist vs AntagonistMorphine
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The Open Structural Biology Journal, 2008, 2, 8-20
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Agonist vs Antagonist
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A fragment of MD simulation showing breaking of D3.32-Y7.43 hydrogen bond (3-7 lock) in the complex morphine – MOR. Morphine phenolic hydroxyl group binds to H6.52. Carbon atoms of morphine are colored in orange. Numbers (in Å) inform about selected distances (showed as dashed lines).
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A whole MD simulation of antagonist complex NTX – MOR. NTX phenolic hydroxyl group is restrained to form a hydrogen bond with H6.52. The simulation shows breaking of D3.32-Y7.43 connection (3-7 lock), break of (TRP) W6.48 – (Ser) S7.46 hydrogen bond and a rotamer swap of W6.48. Numbers (in Å) inform about selected distances (showed as dashed lines).
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Morphine Pharmacokinetics
O
N
HOOH
H
O
N
O OH
H
O
N
HOO
H
O
HOHO
HO
HO
O
OHOH
OH
OH
Phase 2
Glucuronidation
Morphine-3-glucuronide
Morphine-6-glucuronide
Bioavaliability (humans) 24% PO; 100% IM, 100% IV; 60% transnasalRapid tissue distribution~ 70% subjected to Phase 2 metabolism
M3G:morphine 6:1 M6G:morphine 1:1does not bind to MOR psychoactive
Morphine (not glucuronides) transported across BBB by P-glycoprotein (P-gp)
Medicinal Research Reviews, 2005, 25, 521
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Heroin Hydrolysis
Heroin does not bind to opioid receptorsIn vivo t1/2 in blood of heroin: 4 - 5 minutes
6-AM: 30 minutes
Step 1 - human serum cholinesterase (EC 3.1.1.8) & arylesterase (EC. 3.1.1.2)
Human liver carboxyesterase 1
Heroin to 6-acetylmorphine kcat/Km = 314 mM-1min-1
6-acetylmorphine to morphine kcat/Km = 22 mM-1min-1