Post on 26-Dec-2015
Opioid AnalgesicsOpioid Analgesics
Mallika DossMallika Doss
April 10, 2008April 10, 2008
OverviewOverview• HistoryHistory• MorphineMorphine
– SAR of MorphineSAR of Morphine– Drug Dissection of MorphineDrug Dissection of Morphine
• Morphine AnaloguesMorphine Analogues• Opioid Receptors & Receptor BindingOpioid Receptors & Receptor Binding• Agonists and AntagonistsAgonists and Antagonists• Why you feel “happy” Why you feel “happy” • Endogenous Opioid peptidesEndogenous Opioid peptides• The FutureThe Future
The HistoryThe History• First use in MesopotamiaFirst use in Mesopotamia• First recorded use in ChinaFirst recorded use in China• 632 AD – Opium reaches Spain, Persia, and India632 AD – Opium reaches Spain, Persia, and India• 1717thth century – Tobacco comes to China century – Tobacco comes to China• 1644 – Chinese emperor bans tobacco1644 – Chinese emperor bans tobacco• 1919thth century – China closes its doors to the world century – China closes its doors to the world• Deprived of tobacco, Chinese people start smoking opium!Deprived of tobacco, Chinese people start smoking opium!• Opium production in China couldn’t keep up with demand. Opium production in China couldn’t keep up with demand.
British East India company sees opportunity.British East India company sees opportunity.• 1830s – 1830s – ££1 million of opium smuggled into China via Port 1 million of opium smuggled into China via Port
Canton.Canton.
The HistoryThe History• Chinese authorities burnt down the port; British traders Chinese authorities burnt down the port; British traders
outraged.outraged.• 1839-42 – Opium Wars; Chinese were defeated and 1839-42 – Opium Wars; Chinese were defeated and
forced to lease trading port to Britain.forced to lease trading port to Britain.• 1919thth century – Opium dens common in Britain. century – Opium dens common in Britain.• 1882 – Addictive properties of opium discovered but 1882 – Addictive properties of opium discovered but
largely ignored.largely ignored.• 1909 – IOC set up to curb opium production1909 – IOC set up to curb opium production• 1924+ – Opium production went underground1924+ – Opium production went underground
MorphineMorphine• Named after the Greek God, Named after the Greek God,
Morpheus (God of dreams)Morpheus (God of dreams)• Good for treating dull, constant pain Good for treating dull, constant pain
rather than sharp, periodic painrather than sharp, periodic pain• Side effects:Side effects:
– ExcitationExcitation– EuphoriaEuphoria– NauseaNausea– Pupil constrictionPupil constriction– ConstipationConstipation– Tolerance and DependenceTolerance and Dependence– Depression of breathingDepression of breathing
Maximize
Minimize
Morphine - SARMorphine - SAR
Phenolic OH Phenolic OH
6-alcohol 6-alcohol Double bond at 7-8 Double bond at 7-8
N-methyl group N-methyl group
Aromatic ring Aromatic ring
Ether bridge Ether bridge
RequiredRequired
Not RequiredNot Required
Not RequiredNot Required
RequiredRequired
RequiredRequired
Not RequiredNot Required
Morphine – Drug DissectionMorphine – Drug Dissection
E E
D D
Loss of activity Loss of activity Activity retained Activity retained
C C
BB
MorphinansMorphinansBenzomorphansBenzomorphans4-phenylpiperidines4-phenylpiperidinesMethadoneMethadone
Morphine Analogues - CodeineMorphine Analogues - Codeine
• How it’s relatedHow it’s related– Methyl ether of morphineMethyl ether of morphine
• ActivityActivity– 20% that of morphine20% that of morphine
• Pro-drug of morphinePro-drug of morphine– Metabolized by O-Metabolized by O-
demethylation in the liver demethylation in the liver to make morphineto make morphine
Codeine
Morphine Analogues - CodeineMorphine Analogues - Codeine
• Treats:Treats:– Moderate painModerate pain– CoughsCoughs– diarrheadiarrhea
• Marketed as:Marketed as:– TylenolTylenol®® with Codeine with Codeine– HydrocodoneHydrocodone– VicodinVicodin® (with ® (with
Thebaine)Thebaine)
Morphine Analogues - HeroineMorphine Analogues - Heroine• How it’s related:How it’s related:
– 3,6-diacetyl ester of morphine3,6-diacetyl ester of morphine• Activity:Activity:
– 2x that of morphine2x that of morphine• Polar groups are hidden, making it Polar groups are hidden, making it
easy to cross BBB.easy to cross BBB.• Treats:Treats:
– Pain in terminally ill patientsPain in terminally ill patients• Side effectsSide effects
– Euphoria, addiction, toleranceEuphoria, addiction, tolerance• Marketed as:Marketed as:
– Heroin, “dope”Heroin, “dope”
Heroine
Morphine Analogues - HeroineMorphine Analogues - Heroine6-acetylmorphine6-acetylmorphine• How it’s related:How it’s related:
– 6-acetyl of morphine6-acetyl of morphine• ActivityActivity
– 4x that of morphine!4x that of morphine!• Polarity decreased, but phenol is Polarity decreased, but phenol is
ready to bind receptorready to bind receptor• Side effects: Very potent!!Side effects: Very potent!!
– Euphoria, addiction, etc.Euphoria, addiction, etc.• Marketed as:Marketed as:
– NOTHING! It’s banned from NOTHING! It’s banned from production in many countriesproduction in many countries
6-acetylmorphine
Morphine Analogues - MorphinansMorphine Analogues - Morphinans• How it’s related:How it’s related:
– Ether bridge removedEther bridge removed• Activity:Activity:
– 5x that of morphine5x that of morphine• Advantage: Advantage:
– It can be taken orallyIt can be taken orally– Lasts longerLasts longer– Easier to synthesizeEasier to synthesize
• Side effects:Side effects:– High toxicity, comparable dependenceHigh toxicity, comparable dependence
• Marketed asMarketed as– Levo-Dromoran®Levo-Dromoran®
Levorphanol
Morphine Analogues - Morphine Analogues - BenzomorphansBenzomorphans
• How it’s relatedHow it’s related– Rings C and D removedRings C and D removed
• ActivityActivity– 4x + that of morphine4x + that of morphine
• AdvantagesAdvantages– No addictive propertiesNo addictive properties– Does not depress breathingDoes not depress breathing– Lasts longerLasts longer
• Side effectsSide effects– Hallucinogenic Hallucinogenic
• Marketed asMarketed as– Prinadol, NorphenPrinadol, Norphen– Fortal, Talwin NXFortal, Talwin NX Pentazocine
Phenazocine
Morphine Analogues – 4-Morphine Analogues – 4-phenylpiperidinesphenylpiperidines
FentanylFentanyl• How it’s related:How it’s related:
– Rings B,C,D removedRings B,C,D removed• Activity:Activity:
– 100x that of morphine100x that of morphine• Advantages:Advantages:
– Cross BBB efficientlyCross BBB efficiently– Really easy to makeReally easy to make– Rapid onset, short durationRapid onset, short duration– Can be administered any Can be administered any
way (IV, oral, transdermal, way (IV, oral, transdermal, buccal)buccal)
Fentanyl
Morphine Analogues – 4-Morphine Analogues – 4-phenylpiperidinesphenylpiperidines
• Used for:Used for:– Anesthesia Anesthesia – Chronic pain managementChronic pain management
• Side effects:Side effects:– Sudden respiratory depressionSudden respiratory depression– More addictive than heroinMore addictive than heroin– Less euphoria, more sedationLess euphoria, more sedation
• Marketed as:Marketed as:– Sufenta (used in Sufenta (used in ♥♥ surgery) surgery)– Carfentanil (used in vet practice)Carfentanil (used in vet practice)– ““Percopop”, OxyContin, “magic” (heroin/cocaine)Percopop”, OxyContin, “magic” (heroin/cocaine)
Morphine Analogues - MethadoneMorphine Analogues - Methadone• How its related:How its related:
– Rings B,C,D,E openedRings B,C,D,E opened• ActivityActivity
– < Morphine< Morphine• Used to:Used to:
– Ween addicts off heroine or morphineWeen addicts off heroine or morphine• Advantages:Advantages:
– Can be given orallyCan be given orally– Less severe side effectsLess severe side effects
• Marketed asMarketed as– Dolophine®, Amidone®, Methadose® Dolophine®, Amidone®, Methadose®
Morphine analogues - NaltrexoneMorphine analogues - Naltrexone• How it’s related:How it’s related:
– Cyclopropylmethylene added Cyclopropylmethylene added to morphineto morphine
• Activity:Activity:– None?!None?!
• Morphine antagonistsMorphine antagonists• Used to treat:Used to treat:
– Morphine overdoseMorphine overdose– Heroin addicts post-rehabHeroin addicts post-rehab
• Advantages:Advantages:– No side effectsNo side effects
• Marketed as:Marketed as:– Revia, Depade, VivitrolRevia, Depade, Vivitrol
Nalorphine
Naltrexone
Agonists and AntagonistsAgonists and Antagonists
Axial Agonist binding area
Equatorial Antagonist binding area
SIDE NOTE:SIDE NOTE:
• Other factors important to receptor binding:Other factors important to receptor binding:– StereochemistryStereochemistry
• Enantiomers of many of the analogues were tested Enantiomers of many of the analogues were tested for analgesic activity. Overall, they didn’t have any.for analgesic activity. Overall, they didn’t have any.
– RigidificationRigidification• Used to maintain active formation and eliminate Used to maintain active formation and eliminate
alternative conformationsalternative conformations• Increases selectivity for receptorsIncreases selectivity for receptors
Opioid ReceptorsOpioid Receptors
• Receptor-binding Receptor-binding motif:motif:– Phenol OHPhenol OH– Aromatic ringAromatic ring– Amine groupAmine group
Opioid ReceptorsOpioid ReceptorsReceptor
typeLocation Effects
μ Brain, spinal cord
Analgesia, Respiratory depression, euphoria, addiction, ALL pain messages blocked
κ Brain, spinal cord
Analgesia, sedation, all non-thermal pain messages blocked
δ Brain Analgesia, antidepression, dependence
Most Most strongly strongly
binds binds morphinemorphine
Best bet Best bet for a safe for a safe analgesicanalgesic
Receptor binding - Receptor binding - μμ
Morphine
• Opening of the KOpening of the K++ channel channel hyperpolarizes the hyperpolarizes the membranemembrane
•Action potential not Action potential not sentsent
•CaCa+2+2 not released not released
•Reduces Reduces neurotransmitter neurotransmitter releaserelease
Hyper-polarized!
μ
Receptor Binding - Receptor Binding - κκ
Morphine• Binding causes Binding causes closing of Ca+2 closing of Ca+2 channelschannels
• Neurotransmitters Neurotransmitters not releasednot released
• Pain message not Pain message not sentsent
κ
Why you feel “happy”Why you feel “happy”
Why you feel “happy”Why you feel “happy”• Heroin modifies the action of dopamine in the brain. Heroin modifies the action of dopamine in the brain. • Once crossing the blood-brain barrier, heroin is Once crossing the blood-brain barrier, heroin is
converted to morphine, which acts as an agonist. converted to morphine, which acts as an agonist. • This binding inhibits the release of GABA from the nerve This binding inhibits the release of GABA from the nerve
terminal, reducing the inhibitory effect of GABA on terminal, reducing the inhibitory effect of GABA on dopaminergic neurones. dopaminergic neurones.
• The increased activation of dopaminergic neurones and The increased activation of dopaminergic neurones and the release of dopamine into the synaptic cleft results in the release of dopamine into the synaptic cleft results in activation of the post-synaptic membrane.activation of the post-synaptic membrane.
• Continued activation of the dopaminergic reward Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ pathway leads to the feelings of euphoria and the ‘high’ associated with heroin use. associated with heroin use.
Endogenous Opioid PeptidesEndogenous Opioid Peptides
• Your body’s natural Your body’s natural painkillerspainkillers
• Have a preference for the Have a preference for the δδ--receptorreceptor
• Alternative method of pain Alternative method of pain relief relief inhibit the inhibit the peptidases that degrade peptidases that degrade them them thiorphan (still new) thiorphan (still new)
• 3 types of EOPs:3 types of EOPs:– EnkephalinsEnkephalins– DynorphinsDynorphins– EndorphinsEndorphins
Met-enkephalin
The FutureThe Future
• Find an agonist that solely binds to the Find an agonist that solely binds to the κκ-receptor-receptor• Explore the Explore the μμ-receptor subtypes further to see if any of -receptor subtypes further to see if any of
them don’t cause harmful side effectsthem don’t cause harmful side effects• Peripheral opiate receptors – avoid BBB obstaclePeripheral opiate receptors – avoid BBB obstacle• Block postsynaptic receptors involved in the transmission Block postsynaptic receptors involved in the transmission
of a pain signalof a pain signal• GABAGABA• Agonists for the cannabinoid receptorAgonists for the cannabinoid receptor
ReferencesReferences