Chemistry d Ch i t and the Nervous System

DimaBerbasov May,15,2009

Whattoexpectfromthispresentation What to expect from this presentation

Medicinalchemistry Biochemistry Total synthesis Totalsynthesis

Ouline
Nervoussystem
Classification Neurons Ionic and metabotropic receptors Ionicandmetabotropic

Neurotransmitters
Acetylcholin andrelatedchemicals Monoaminesandrelatedchemicals Aminoacids andrelatedchemicals

Conclusion

Human Nervous System

Neuron

http://en.wikipedia.org/wiki/Neuron

Some facts

1011 neurons 1015synapses synapticgap2x105 mm

Ions channels and G-proteins G proteins

Ionotropic receptor

Metabotropic receptor

Nicotinic Acetylcholine receptor (nAChr)

Cobra venom action

Neurotransmitters (NT)

O N O Acetylcholine

Acetylcholine

First isolated in 1914 by Henry Dale, Otto Loewi. Both received 1936 Nobel prize in Medicine In the PNS, acetylcholine activates muscles, and is a major h S l h li i l di j neurotransmitter in the autonomic nervous system. In the CNS, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause i h h li i hi h d excitatory actions.

AcetylCholine receptors nicotinic acetylcholine receptors nAChR nicotinicacetylcholinereceptors

290 kD 5 b it 290kDa,5subunitsaroundcentralpore. d t l SimilaritieswithGABA,glycine,5HTreceptors Nicotine,choline,epibatidine affinity

Muscarinic acetylcholinereceptorsmAChR y p

Epibatidine and Tebanicline andTebanicline

IsolatedfromPhantasmalpoisonfrog

1976 isolated 1986structureelucidated 200timesmorepotentthenmorphine 200 times more potent then morphine

Newleaddrug
50timemorepotentthanmorphine, Binds nAchR not opiod receptors BindsnAchR,notopiod Didnotgofarther thanPhaseIItrial.Due togastrointestinalsideeffects

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

Synthesis of Tebanicline

Sorbera, L.A., Revel, L., Leeson, P., Castaner, J. Drugs of the Future 2001, 26(10): 92

Tetrodotoxin and Batrachotoxin

blockNachannelsinneurons InhibitorofnAChr
OH HO O HO HN HN O O OH

OH N H OH

Y.Kishi 1972racemic J.Am.Chem.Soc 94 (26):9217 IsobeJ.Am.Chem.Soc 125 (29):8798 DuBois 2003asymetric J.Am.Chem.Soc 125 (38):11510

Kurosu,M.;Marcin,L.R.;Grinsteiner,T.J.;Kishi,Y. J.Am.Chem.Soc. 1998, 120, 6627.

Synthesis of (+)-Tetradotoxin

OH HO HO HN HN O O OH

OH N H OH

Hinman, A.; Hinman A ; Du Bois J 2003 J Am. Chem. Soc 125 11510 Bois, J. J. Am Chem 125,

Synthesis of (+)-Tetradotoxine

Hinman, A.; Du Bois, J. 2003 J. Am. Chem. Soc 125, 11510

Synthesis of ()-Batrachotoxine

Kurosu,M.;Marcin,L.R.;Grinsteiner,T.J.;Kishi,Y.J.Am.Chem.Soc. 1998, 120, 6627.

Diels-Alder Cyclization

OH S S X R H Y

Kurosu,M.;Marcin,L.R.;Grinsteiner,T.J.;Kishi,Y.J.Am.Chem.Soc. 1998, 120, 6627.

Completion

Kurosu,M.;Marcin,L.R.;Grinsteiner,T.J.;Kishi,Y.J.Am.Chem.Soc. 1998, 120, 6627.

Muscarinic acetylcholine receptors mAChr Stimulatedbymuscarine andacetylcholine Stimulated by muscarine and acetylcholine Inhibitedbyatropine Metabotropic i b i inaction i LocatedinCNS,heart,lungs,sweatglands

Muscarine
HO Br AD-mixtBUOH/H2O CH3SO2NH2 0 C HO HO HO HO 52% (40% ee) 60 a 59% : HO 40 Br H HO Br AD-mixtBUOH/H2O CH3SO2NH2 0 C HO OH 60% (90% ee) H 27 a 58% : 73 O H H HO Br b O H b O H HO NMe3 O BrH H (+)-epi-muscarine HO O H H (+)-epiallo-muscarine NMe3 Brb HO NMe3 O BrH H (-)-allo-muscarine H O H b H O HO NMe3 Br-

H (+)-muscarine

(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

Hartung, J.; Kuz., P.; Laug. S.; Schmidt, P. Synlett, 2003, 1, 51

Donepezil

Acetylcholineesteraseinhibitor Discoveredlate1980s Discovered late 1980s Introduction1996(Eisai) MaintreatmentofAlzheimersdesease

Monoamines

OH NH2 HO OH Norepinephrine HO N H Serotonin NH2 HO OH Dopamine

NH2

N O

NH2 N H histamine

O N H Melatonin

N H

Monoamines

Catecholamines Biosynthetic Relationship

Levodopa (L-DOPA) (L DOPA)

2 2

Discovered 1960s Introduction in 1970 (Roche) racemic Cross blood-brain barrier while dopamine not 2001- William S K 2001 Willi S. Knowles got Nobel prize in Chemistry with R. N l t N b l i i Ch i t ith R Noyori, B Sh l f the i B. Sharpless for th development of asymetric hydrogenation

Monsanto Process of Levodopa

OCH3 P Cy CAMP CH3

WilliamS.Knowles Nobellectureof2001 N b ll f 2001

Dopamine

1958discoveredbyArvind Calrsson 2000NobelprizeinMedicine 1910firstsynthesis 1910 fi t th i Functions

Behaviorandconditions Motoractivity Motivationandreward Mood,learning,attention

Dopamine Receptors
Excitory D1 most abundant, neuronal growth, D2-mediator.
H H N HO NH H HO OH Dihydrexidine HO Cl HO Fenoldopam

Inhibitory D2 renal system, antipsychotic drugs target Antagonist: risperidone, h l i id haloperidol id l D3, limbic system D4, signals cardial output g p without changing heart rate, ADHD

D5- limbic region of brain (responsible for emotions) 1 Antagonist

Haloperidol Synthesis

Anjaiah, S.; Chandrasekhar, S.; Gree, R. Adv. Synth. Catal. 2004, 346, 1329

MPTP (Herbicide Cyperquat)

Bindes todopaminetransporter Kills dopamine receptors Killsdopaminereceptors InitiateParkinsondesease inmonkeysandrats

NarcoticdrugsamongDopamineand Opioid receptors d

HO N O O O HO Cocaine O Morphin First isolated in 1803 O N O AcO N

AcO Heroin sold as cough suppresant by Bayer till 1910 was legal in USA till 1924 O Et N N Fentanyl

O O HN

CH3 H CH3 O

OH

MDMA (ecstasy)

Tetrahydrocannabinol cannabinoid receptor

The last synthesis of Cocaine

Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305

Salvinorin A (-opioid receptor agonist) ( p p g )

O O bis-Michael O Me OH

O AcO

H Me

O O

O BOMO

Me

MeO2C

Me

(OMe)2HC

O O BOMO Me (OMe)2HC O Me O O

Scheerer,J.R.;Lawrence,J.F.;Evans,D.A.J.Am.Chem.Soc. 2007,129,8968

Bis-Michael Addition Cascade

entry 1 2

R H CH(OMe)2

yield(%) 95 95

dr 95:5 95 5 >95:5

Scheerer,J.R.;Lawrence,J.F.;Evans,D.A.J.Am.Chem.Soc. 2007,129,8968

Transannular Cyclization Analysis

H H BOMO (MeO)2HC O Me Me O H H H H Ar O O O

bis-Michael (Stepwise) O O BOMO Me (OMe)2HC H H BOMO (MeO)2HC O Me Me H H O H O Ar O O Me O O TBAF -78 to 5 C (OMe)2HC Me O BOMO Me O O OH

exo-Diels-Alder (Concerted)

Scheerer,J.R.;Lawrence,J.F.;Evans,D.A.J.Am.Chem.Soc. 2007,129,8968

OnepotsynthesisofFentanyl One pot synthesis of Fentanyl

Opioud receptoragonist Analgesic Derivativesusedinheartsurgery, g Sedationofbiganimals

Gupta,P.K.;Ganesan,K.;Pande,A.;Malhorta,R.J.Chem.Res. 2005,452

Antidepresants
Monoamine Oxidize Inhibitores (MAOIs) MonoamineOxidizeInhibitores (MAOIs) (historicallyfirst) Tricyclic Antidepressants (TCA) (very common Antidepressants(TCA)(verycommon antidepressants) S l i S SelectiveSerotoninReuptakeInhibitors(SSRIs) i R k I hibi (SSRI ) SerotoninNorepinephrine ReuptakeInhibitors (SNRIs)

Common Antidepressants

Dopamine and Serotonin pathways

http://wpcontent.answers.com/wikipedia/en/1/1c/Dopamineseratonin.gif

Serotonin or 5-hydroxytryptamine, 5-HT

Modulate Anger Bodytemperature Mood Sleep Apetite Metabolism Vomiting

Release raphe nuclei Receptors 7receptors Onlyone5HT3 isionotropic y p Othersmetabotropic

Lysergicaciddiethylamide(LSD)

5HT2A serotoninreceptor firstsynthesizedinNovember16,1938byDr.Albert Hoffmann,publishedin1943 Hoffmann published in 1943

Antipsychotics and Antianxiety agents

Antipsychotics
N Cl N N N O N O O Cl HO S SeroquelTM CH3 N N N NH N CH3 S H Olanzapine (ZyprexaTM) O Apiprazole (AbilifyTM) HN O Ziprasidone (GeodonTM) O Cl N N Cl O2N Clonazepam (KlonopinTM) Cl Alprazolam (XanaxTM) Cl N N N N S O NH N N N N CH3 Buspirone (BuSparTM) N N N

N H Clozapine (ClozarilTM) N Cl N N

Antianxiety Agents

Aminoacids as Neurotransmitters asNeurotransmitters

Glutamate

Mostabundantneurotransmitter(90%) BindstoNMDAreceptors Binds to NMDA receptors Responsibleforsynapticplasticity Learningandmemory Implicatedinepilepticseizures Implicated in epileptic seizures

GABA

Secondmostabundantneurotransmitter(9%) GADisincerebellumandpancreas GAD is in cerebellum and pancreas Chiefinhibitoryneurotransmitter GABAAChlorinetransmiters GABAB metabotropic receptor

DrugsrelatedtoGABAreceptors Drugs related to GABA receptors

Ethanol Barbiturates Benzodiazepine di i Valleriana Theanine (grean tea)

Barbiturates and Benzodiazepines

Conclusion
Correlationbetweenneurotransmittersanddrug g candidates(Epibatidine andTebanicline) Recognizablepartofcertaintypesofspecifically actingdrugs(benzodiazepines,barbituratesetc) 11Industrialandtotalsynthesisofdrugs discussed Importantneurotransmitterswerecovered