dima berbasov- chemistry and the nervous system

8/3/2019 Dima Berbasov- Chemistry and the Nervous System

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em s ry anthe Nervous

System

Dima Berbasov

May, 15, 2009



• Medicinal chemistry

• Biochemistry

•



• Nervous system

– Classification – Neurons

–

• Neurotransmitters – Acetylcholin and related chemicals

– Monoamines and related chemicals

– Aminoacids and related chemicals

• Conclusion



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



Some facts

10

11‐

neurons

1015‐synapses

synaptic gap 2x10‐5

mm



O

O

N

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

neurotransmitter in the autonomic nervous system.

• In the CNS, acetylcholine and the associated neurons form a

neurotransmitter system, the cho inergic system, which tends to causeexcitatory actions.



•

– a, su un ts aroun centra pore.

Similarities with GABA, glycine, 5HT receptors

– Nicotine, choline, epibatidine affinity

• Muscarinic acet lcholine rece tors mAChR



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

block Na channels in neuronsInhibitor of nAChr

O

OH

OHO

HO

HN NHOH

HN

HO

OH

• 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.



Synthesis of (+)-Tetradotoxin

O

OH

O

HN N OHHN

HO

OH

, . , . . . . ,



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

OS

OH

HY

R

X

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.



•

• Inhibited by

atropine

• Meta otropic in action

• Located in

CNS,

heart,

lungs,

sweat

glands



• Acetylcholine esterase inhibitor

’

• Introduction 1996 (Eisai)

• Main treatment of Alzheimer’s desease



HO

NH2

OH

HO

NH2

OHNorepinephrine Dopamine

NH2HO NH

O

O

N

NH

2

histamine

NH

Serotonin

NH

Melatonin

Monoamines



-

2

2

• Discovered 1960’s

• Introduction in 1970 (Roche) racemic

• Cross blood-brain barrier while dopamine not

• - am . now es got o e pr ze n em stry w t . oyor , . arp ess or t e

development of asymetric hydrogenation



Monsanto Process of Levodopa

OCH3

PCH3

William S. Knowles

CyCAMP

o e ecture o



1958 discovered by Arvind Calrsson

2000

Nobel

prize

in

Medicine rs syn es s

Functions – Behavior and conditions

– Motor activity

– Motivation and reward

– Mood, learning, attention



Dopamine Receptors

• Excitory

– D1 most abundant,

• Inhibitory

– D2 renal system,

neuronal growth,

D2-mediator.

antipsychotic drugs target

Antagonist:HO

r sper one, a oper o

–

N

HOOH

H

NH

HOCl

HO

– D5- limbic region of brain

(responsible for emotions)

,

– D , si nals cardial out ut

Dihydrexidine Fenoldopam

1 Antagonist without changing heartrate, ADHD



An aiah S. Chandrasekhar S. Gree R. Adv. S nth. Catal. 2004 346 132



+

• Bindes to dopamine transporter

• Initiate Parkinson desease in monkeys and rats



Narcotic drugs among Dopamine and

Opioid receptors

N

O

O

HO

NO

AcO

NO

O

OCocaine

HO

MorphinFirst isolated

in 1803

AcOHeroin

sold as coughsuppresant

by Bayer till 1910

in USA till 1924

CH3O

OH

H

H

NN

O

Et

CH3

MDMA (ecstasy)

O

Tetrahydrocannabinolcannabinoid receptor

Fentanyl



The last synthesis of Cocaine

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



Salvinorin A

-o ioid rece tor a onistO

O

OOO

BOMOMe

bis-Michael

OO

OAcO

H H

OHMe

(OMe)2HCMeMeO2C

Me

O

O

O

Me O

BOMO

(OMe)2HC

Scheerer, J.

R.;

Lawrence,

J.

F.;

Evans,

D.

A.

J. Am. Chem. Soc. 2007,

129,

8968



Bis-Michael Addition Cascade

entry R yield(%) dr

:

2 CH(OMe)2 95 >95:5

Scheerer, J.R.;

Lawrence,

J.F.;

Evans,

D.A.

J. Am. Chem. Soc. 2007,

129,

8968



‐Opioud receptor agonist

Analgesic

Derivatives used in heart surgery,

Sedation of bi animals

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



•

(historically first)

antidepressants)

• Se ective Serotonin Reupta e In i itors SSRIs

• Serotonin‐Norepinephrine Reuptake Inhibitors

(SNRIs)

C A i



Common Antidepressants



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



Serotonin or 5-hydroxytryptamine, 5-HT

Modulate Release

–

– Body temperature

– Mood Receptors

– Sleep – Apetite

– Metabolism

7 receptors

Only one 5‐HT is ionotropic

– Vomiting Others metabotropic



Lysergic acid diethylamide (LSD)

• 5‐HT2A serotonin

receptor

• first synthesized in November 16, 1938 by Dr. Albert ,



• Most abundant neurotransmitter (90%)

•

• Responsible for

synaptic

plasticity

• Learning and memory

•



• Second most abundant neurotransmitter (9%)

•

• Chief inhibitory

neurotransmitter

• GABA A‐Chlorine transmiters

• GABAB‐ metabotropic receptor



•

• Barbiturates

• Benzo iazepine

• Valleriana• Theanine (grean tea)



• Correlation between neurotransmitters and dru

candidates (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

dima berbasov- chemistry and the nervous system

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