chemistry of the nervous system - michigan state university · pdf fileneurotransmitter in the...
TRANSCRIPT
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Ch i t dChemistry andthe Nervous
System
Dima Berbasov
May, 15, 2009
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What to expect from this presentationWhat to expect from this presentation
• Medicinal chemistry
• Biochemistry
• Total synthesisTotal synthesis
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OulineOuline
• Nervous system– Classification– Neurons– Ionic and metabotropic receptorsIonic and metabotropic receptors
• Neurotransmitters– Acetylcholin and related chemicals– Monoamines and related chemicals– Aminoacids and related chemicals
• Conclusion
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Human Nervous SystemHuman Nervous System
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NeuronNeuron
http://en.wikipedia.org/wiki/Neuron
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Some facts
10 11‐ neurons1015‐synapses
synaptic gap 2x10‐5
mm
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Ions channels and G-proteinsIons channels and G proteins
Ionotropic receptor Metabotropic receptor
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Nicotinic Acetylcholine receptor (nAChr)Nicotinic Acetylcholine receptor (nAChr)
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Cobra venom actionCobra venom action
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Neurotransmitters (NT)Neurotransmitters (NT)
O
ON
Acetylcholine
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AcetylcholineAcetylcholine
• First isolated in 1914 by Henry Dale, Otto Loewi. Both received 1936 Nobel prize in Medicine
h S l h li i l d i j• In the PNS, acetylcholine activates muscles, and is a majorneurotransmitter in the autonomic nervous system.
• In the CNS, acetylcholine and the associated neurons form a i h h li i hi h dneurotransmitter system, the cholinergic system, which tends to cause
excitatory actions.
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AcetylCholine receptorsAcetylCholine receptors
• nicotinic acetylcholine receptors nAChRnicotinic acetylcholine receptors nAChR
290 kD 5 b it d t l– 290 kDa, 5 subunits around central pore. Similarities with GABA, glycine, 5HT receptors
– Nicotine, choline, epibatidine affinity
• Muscarinic acetylcholine receptors mAChRy p
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Epibatidine and TebaniclineEpibatidine and Tebanicline• Isolated from Phantasmal poison frog
1976 ‐ isolated1986 ‐structure elucidated200 times more potent then morphine200 times more potent then morphine
• New lead drug • 50 time more potent than morphine,• Binds nAchR not opiod receptors• Binds nAchR, not opiod receptors• Did not gofarther than Phase II trial. Due to gastrointestinal side effects
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E.J. Corey Synthesis of Epibatidine
Corey, E. J.; Loh, T. P.; Achyutha, S.; Daley, D. C.; Sarshar, S. J. Org. Chem. 1993, 58, 5600
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Synthesis of Tebanicline
Sorbera, L.A., Revel, L., Leeson, P., Castaner, J. Drugs of the Future 2001, 26(10): 92
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Tetrodotoxin and Batrachotoxinblock Na channels in neurons
Inhibitor of nAChr
O
OH
OHO
HO
HN NH
OHHN
HOOH
OHO
• Y. Kishi 1972 racemic• J. Am. Chem. Soc 94 (26): 9217• Isobe J. Am. Chem. Soc 125 (29): 8798• Du Bois 2003 asymetric• J. Am. Chem. Soc 125 (38): 11510
Kurosu, M.; Marcin, L.R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627.
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Synthesis of (+)-Tetradotoxin
O
OH
OHO
HO
HN NH
OHHN
HOOH
OHHO
HHN
Hinman A ; Du Bois J 2003 J Am Chem Soc 125 11510Hinman, A.; Du Bois, J. 2003 J. Am. Chem. Soc 125, 11510
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Synthesis of (+)-Tetradotoxine
Hinman, A.; Du Bois, J. 2003 J. Am. Chem. Soc 125, 11510
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Synthesis of (±)-Batrachotoxine
Kurosu, M.; Marcin, L.R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627.
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Diels-Alder Cyclization
O
S
S
OH
S
HY
RX
Kurosu, M.; Marcin, L.R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627.
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Completion
Kurosu, M.; Marcin, L.R.; Grinsteiner, T. J.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 6627.
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Muscarinic acetylcholine receptors mAChrMuscarinic acetylcholine receptors mAChr
• Stimulated by muscarine and acetylcholineStimulated by muscarine and acetylcholine
• Inhibited by atropine
b i i i• Metabotropic in action
• Located in CNS, heart, lungs, sweat glands
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Muscarine
AD-mix- HO HO OBr
HO
H H
b60 O
NMe3
HO
H H Br-AD-mix-
tBUOH/H2OCH3SO2NH2
0 °CHO HO
HO
52% (40% ee)
a H H
OBr
HO
H H
b40
:59%
H H(+)-muscarine
ONMe3
HO
H H Br-
HO OBr
HOb
27
H H
ONMe3
HO
H H Br-
(-)-allo-muscarine
AD-mix-
tBUOH/H2OCH3SO2NH2
0 °COH
HO
60% (90% ee)
Oa H H
OBr
HO
H H
b
27
73
:58%
OH H Br
ONMe3
HO
H HBr-
(+)-epi-muscarine
OH H
(a) TBHP, pyHBr, CHCl3, 10 mol% of VOL(OEt)(EtOH)[L = N-(hydroxyphenyl)salicylideneimine dianion], 20 °C, 6 h;(b) NMe3, EtOH, 60 °C, 7 d
H H(+)-epiallo-muscarine
Hartung, J.; Kuz., P.; Laug. S.; Schmidt, P. Synlett, 2003, 1, 51
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DonepezilDonepezil
• Acetylcholine esterase inhibitor• Discovered late 1980’s• Discovered late 1980’s• Introduction 1996 (Eisai)• Main treatment of Alzheimer’s desease
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MonoaminesMonoamines
HO
NH2
OH
HOOH
NH2
NHOHNorepinephrine
OH
Dopamine
NH2HO NHO
O
N
NH
NH2
histamine
NH
SerotoninNH
Melatonin
Monoamines
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Catecholamines Biosynthetic RelationshipCatecholamines Biosynthetic Relationship
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Levodopa (L-DOPA)Levodopa (L DOPA)
2
2
• Discovered 1960’s• Introduction in 1970 (Roche) racemic• Cross blood-brain barrier while dopamine not
2001 Willi S K l t N b l i i Ch i t ith R N i B Sh l f th• 2001- William S. Knowles got Nobel prize in Chemistry with R. Noyori, B. Sharpless for the development of asymetric hydrogenation
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Monsanto Process of Levodopa
OCH3
PCH3
William S. KnowlesN b l l f 2001
PCy
CAMP
Nobel lecture of 2001
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DopamineDopamine
1958 discovered by Arvind Calrsson2000 Nobel prize in Medicine1910 fi t th i1910 first synthesisFunctions
– Behavior and conditions– Motor activity– Motivation and reward– Mood, learning, attention
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Dopamine Receptors
• Excitory– D1 most abundant,
• Inhibitory– D2 renal system,
neuronal growth, D2-mediator.
antipsychotic drugs targetAntagonist: i id h l id lHH
HO
risperidone, haloperidol
– D3 limbic system
HN
HO
H
OH
H
NH
HOCl
HO
– D5- limbic region of brain (responsible for emotions)
D3, limbic system
– D4, signals cardial output
Dihydrexidine Fenoldopam
1 Antagonist4 g p
without changing heart rate, ADHD
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Haloperidol SynthesisHaloperidol Synthesis
Anjaiah, S.; Chandrasekhar, S.; Gree, R. Adv. Synth. Catal. 2004, 346, 1329Anjaiah, S.; Chandrasekhar, S.; Gree, R. Adv. Synth. Catal. 2004, 346, 1329
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MPTP (Herbicide Cyperquat)MPTP (Herbicide Cyperquat)
+
• Bindes to dopamine transporter
• Kills dopamine receptors• Kills dopamine receptors
• Initiate Parkinson desease in monkeys and rats
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Narcotic drugs among Dopamine and dOpioid receptors
NO
O
HO
NO
AcO
NO
O
OCocaine
HOMorphin
First isolatedin 1803
AcOHeroin
sold as coughsuppresant
by Bayer till 1910was legalwas legal
in USA till 1924
CH3
HN
O
O
OH
H
H
NN
OEt
HNCH3O
MDMA (ecstasy)O
Tetrahydrocannabinolcannabinoid receptor
Fentanyl
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The last synthesis of Cocaine
Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305
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Salvinorin A (-opioid receptor agonist)
O
( p p g )O
OO
OBOMO
Mebis-Michael
OO
OAcO
H H
OHMe
(OMe)2HC
O
MeMeO2C
Me
O
MeO
O
O
MeO
Me OBOMO
O(OMe)2HC
Scheerer, J. R.; Lawrence, J. F.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968
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Bis-Michael Addition Cascade
entry R yield(%) dr
1 H 95 95 51 H 95 95:5
2 CH(OMe)2 95 >95:5
Scheerer, J.R.; Lawrence, J.F.; Evans, D.A. J. Am. Chem. Soc. 2007, 129, 8968
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Transannular Cyclization Analysis
OHH
HH H Ar
HBOMO
O
OMeO
H
OMeO
BOMO(MeO)2HC
bis-Michael (Stepwise)
O
O
MeO
Me OBOMO
OO
OH
OBOMO MeTBAF
-78 to 5 °C
O(OMe)2HC
OHMe
(OMe)2HC
OHH
H Ar
Me
H
OHMeO
BOMO(MeO)2HC
H
O
exo-Diels-Alder (Concerted)
Scheerer, J. R.; Lawrence, J. F.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968
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One pot synthesis of FentanylOne pot synthesis of Fentanyl
‐Opioud receptor agonistAnalgesicDerivatives used in heart surgery, Sedation of big animals
• Gupta, P.K.; Ganesan, K.; Pande, A.; Malhorta, R. J. Chem. Res. 2005, 452
g
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AntidepresantsAntidepresants
• Monoamine Oxidize Inhibitores (MAOIs)Monoamine Oxidize Inhibitores (MAOIs) (historically first)
• Tricyclic Antidepressants (TCA) (very common• Tricyclic Antidepressants (TCA) (very common antidepressants)
S l i S i R k I hibi (SSRI )• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Serotonin‐Norepinephrine Reuptake Inhibitors (SNRIs)
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Common Antidepressants
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Dopamine and Serotonin pathwaysDopamine and Serotonin pathways
http://wpcontent.answers.com/wikipedia/en/1/1c/Dopamineseratonin.gif
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Serotonin or 5-hydroxytryptamine, 5-HT
Modulate
Anger
Release
raphe nuclei– Anger
– Body temperature
– Mood
raphe nuclei
Receptors
– Sleep
– Apetite
– Metabolism
7 receptors
Only one 5‐HT3 is ionotropic
– Vomiting
y 3 p
Others metabotropic
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Lysergic acid diethylamide (LSD)
• 5‐HT2A serotonin receptor• first synthesized in November 16, 1938 by Dr. Albert
Hoffmann published in 1943Hoffmann, published in 1943
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Antipsychotics and Antianxiety agents
NN
N
Cl
Antipsychotics
NH
N
Clozapine (ClozarilTM)
Cl
NN
O
O N N
N
S
NN
N
Cl
O
HO
HN
NN
SNCl
N
O
NNN
O
Buspirone (BuSparTM)
OCl ClN
CH3
S
SeroquelTM
HNO
Ziprasidone (GeodonTM)
NHNCl
O2N
NN
Cl
CH3
NHN N
OTM
NH
NN
S CH3TM
Alprazolam (XanaxTM)Clonazepam (KlonopinTM)
Antianxiety Agents
Apiprazole (AbilifyTM)Olanzapine (ZyprexaTM)
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Aminoacids as NeurotransmittersAminoacids as Neurotransmitters
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GlutamateGlutamate
• Most abundant neurotransmitter (90%)• Binds to NMDA receptorsBinds to NMDA receptors• Responsible for synaptic plasticity• Learning and memory• Implicated in epileptic seizuresImplicated in epileptic seizures
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GABAGABA
• Second most abundant neurotransmitter (9%)• GAD is in cerebellum and pancreasGAD is in cerebellum and pancreas• Chief inhibitory neurotransmitter• GABA A‐Chlorine transmitersA• GABAB‐metabotropic receptor
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Drugs related to GABA receptorsDrugs related to GABA receptors
• EthanolEthanol
• Barbiturates
di i• Benzodiazepine
• Valleriana
• Theanine (grean tea)
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Barbiturates and BenzodiazepinesBarbiturates and Benzodiazepines
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ConclusionConclusion
• Correlation between neurotransmitters and drug gcandidates (Epibatidine and Tebanicline)
• Recognizable part of certain types of specifically acting drugs (benzodiazepines, barbiturates etc)
• 11 Industrial and total synthesis of drugs discussed
• Important neurotransmitters were covered