1

CHEM E-120Harvard University Extension School

Neurodegenerative DisordersParkinson’s Disease

March 30, 2011

3/30/11 CHEM E-120

2

Neurodegenerative DiseasesDue to physical degradation of components of the CNS

Parkinson’s - cell death of dopamine producing neurons in the basal ganglia

Alzheimer’s - neuronal cell death and dysfunction on areas of brain involved with memory and cognition

Huntington’s - neuronal death in cortex, basal ganglia, thalamus, and brainstem

Multiple Sclerosis - loss of the myelin (white matter) sheath on axonsneuroinflammatory disease

Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s Disease) general loss of motor system neurons in the spinal cord, brain stem, and motor cortex

Cu-Zn superoxide dismutase (J. Med. Chem. 2010, 53, 1402–1406)

3/30/11 CHEM E-120

3

Motor System

1. Corticospinal tract (formally pyramidal system)descends from the motor cortex terminating in the brainstem and spinal cordvoluntary movement

2. Basal ganglia tract (formally extrapyramidal system)ascend from midbrain cortexself-initiated movement movement sequencingamplitude and velocity of movementautomatic postural and reflex motor activity

Basal Ganglia System

Anatomically divided into 4 structures:a. striatum: caudate nucleus (cognition), putamen (motor), nucleus accumbensb. globus pallidusc. subthalamic nucleusd. substantia nigra

3/30/11 CHEM E-120

4

Thalamus

Cortex

Cortex

3/9/11 CHEM E-120

SN

SN Substantia nigra - extrapyramidal nigrostriatal pathwayGPi internal segment of globus pallidusGPe external segment of globus pallidus

striatum

GPi

GPe

excitoryinhibitory

direct pathway (remove brake)indirect pathway (brake)

subthalamicnucleus

Movement Control and Basal Ganglia – Normal Conditions

GPi and SN tonically active ( movement)

dopamine bindingto D1 and D5 excites direct

dopamine binding to D2, D3, D4 inhibits indirect

5

Thalamus

Cortex

Cortex

3/9/11 CHEM E-120

SN

SN Substantia nigra - extrapyramidal nigrostriatal pathwayGPi internal segment of globus pallidusGPe external segment of globus pallidus

striatum

GPi

GPe

excitoryinhibitory

direct pathway (remove brake)indirect pathway (brake)

subthalamicnucleus

Movement Control and Basal Ganglia – Parkinson’s Disease

GPi and SN tonically active ( movement)

lack of dopamine bindingto D1 and D5 inhibits direct

lack of dopamine binding to D2, D3, D4 disinhibits indirect

reduced

6

Parkinson’s Disease

Characterized by neuronal cell death in the substantia nigra pars compacta (~1% cell loss/year nonparkinson’s individuals)

This leads to a substantial loss of neuronal dopamine in basal ganglia. About 80% of neuronal dopamine is in the basal ganglia.

Clinical onset of Parkinson’s noted when ~ 70% of striatal dopamine is lost. ~ 50 - 60% cell death

Loss of dopamine appears to reduce activity direct pathway increase activity indirect pathway

disruption of direct/indirect cycles

Degeneration of cholinergic, adrenergic, serotonergic systems

3/30/11 CHEM E-120

7

Parkinson’s Disease

Effects ~ 1% of population with onset most likely at 55-65 years of age

Resting tremor of ~ 5 HzUnilateral or asymmetric onset of bradykinesia (abnormallyslow voluntary movements)RigidityPostural disturbance

FRONTLINE My Father, My Brother, and Me 2009http://video.mpbn.net/video/1082086931

OnsetMotorcomplications Resistant Symptoms Cognitive Decline

YEARS0

8 13 20 25

DEATH

3/30/11 CHEM E-120

Current Drugs for Parkinson’s

83/30/11 CHEM E-120

Monoamine Neurotransmitter Levels

9

Dopamine

Norepheniphrine

Serotonin

Amg, amygdala; ACC, nucleus accumbens; AP, area postrema; Cer, cerebellum; CIC, cingular cortex; DMN, dorsal motor nucleus of the vagus nerve; EC, entorhinal cortex; FC, frontal cortex; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus; HI, hippocampus; HY, hypothalamus; LC, locus coeruleus; PU, putamen; Cau, caudate; SN, substantia nigra; PAL, pallidum; POG, parolfactory gyrus; PPN, pedunculopontine nucleus; RN, raphe nuclei; SI, substantia innominata; SC, spinal cord; STN, subthalamic nucleus; VTA, ventral tegmental area.

Nature Reviews Drug Discovery 2006, 5, 845

3/30/11 CHEM E-120

Loss of dopamine transporter

10

[123I]-β-CITDopaScan

Nature Reviews Drug Discovery 2006, 5, 8453/30/11 CHEM E-120

12

Parkinsonism caused by MPTP

Uptake and accumulation in nigrostriatal dopaminergic neurons.

Phase 1 hydrolysis Phase 1 oxidation

3/30/11 CHEM E-120

animal treated daily for 7 days with MPTP (30 mg/kg)PNAS 1985, 82, 2173

N

N

Paraquat

Dopamine Centered Medication Development

12

Loss of dopamine

Clinical replacementof dopamine

L-DOPA

Prevention ofdopamine metabolism

MAO-B inhibitionCOMT inhibition

Substitution of dopamine

D2 type agonistsD1 type agonistsD3 agonistsDAT/Dopamine release

Current medications relieve symptoms but do not alterthe course of the disease

3/30/11 CHEM E-120

L-DOPA

13

Currently the medication of choiceProdrug of dopamine, dopamine cannot cross the BBB whereas L-DOPA is transported by aromatic amino acid transporters

3/30/11 CHEM E-120

1/28/09 CHEM E-120 14

Blood-Brain Barrier (BBB)

A physical barrier that controls the movement of chemicals from extracellular fluid in the body (blood) into the extracellular fluid of the brain.

In the brain the endothelial cells in blood capillaries form a very tight junction that prevents many chemicals from passive diffusion across the capillary cell membrane into the brain.

Lipid-soluble substances can often diffuse across BBB

Active transporters exist in the capillary cell membraneglucoseamino acidshormones

Efflux transporters P-glycoprotein (P-gp)

MRPOrganic anion transporters (OAT3)

Transporters can be on blood side or CNS side of membranes.

1/28/09 CHEM E-120 15

BBB in Capillary Cell

Nature Reviews Drug Discovery 2007, 6, 650

L-DOPA

16

Dopa decarboxylase is a cytoplasmic (soluble) enzyme located throughout the body.

Higher levels outside the CNS that reduce levels of L-DOPA by metabolism before it reached the brain. Often requires dosage of 3-6 gms/day.

Adjunct therapy - peripherally active decarboxlyase inhibitorsSinemet – carbidopa (25mg) and levodopa (100mg) 2-3 times day

Clinical Aspects

Side effects usually due to peripherally generated dopamine“Wearing off” phenomenaIncreasing dosage can lead to dyskinesias – excessive and abnormal involuntary movementsOn/off phenomena Extended release form of Sinemet

3/30/11 CHEM E-120

Metabolic Inhibition and Oxidative Stress

17

Dopamine is readily oxidized to reactive intermediate

Consideration of MPTP suggests that metabolic stress may play a role on Parkinson’s Disease

3/30/11 CHEM E-120

MAO-B Inhibitors

18

Selective, irreversible inhibitor of MAO-B at <10mg/day. MAO-B predominate isoform in CNS.

Used in combination with L-DOPA. Proposed to increase dopamine levels and act as neuroprotective agent.

3/30/11 CHEM E-120

Dopamine Agonists

19

Used alone in early stage Parkinson’s and with L-DOPA in advanced stages

Striatum D1 >> D5 D2 > D3

D2 antagonists know to produce Parkinson-like effectsD1 partial agonists shown not to be effective

D2 agonists therefore of interestD3 agonists were found to posses efficacy

Efficacy of D1 activation appears less than D2 activation making D1 more susceptible to lower dopamine concentrations

Phenotype effects in knockout mice

D1 reduced agonist response, hyperlocomotionD2 Parkinsonian-like motor impairmentD3 HyperactivityD4 reduced locomotion, hypersensitivity to ethanol and stimulantsD5 reduced agonist induced locomotion, startle, and prepulse inhibition

3/30/11 CHEM E-120

Ergot Akaloids – Dopamine Agonist

20

Bromocriptine (Parlodel)1967

D1-type partial agonistD2-type full agonist5-HT agonist

Pergolide (Permax)

D1-type agonistD2-type full agonist5-HT agonist

Cabergoline(Dostinex)

Lisuride

Ki (nM)

D1 D2 D3

Dopamine 2729 146 69

Bromocriptine 120 4.9 30

Cabergoline 1462 1.6 1.3

Lisuride 57 1.2 1.1

Pergolide 447 37 0.863/30/11 CHEM E-120

D3 Agonists – Pramipexole (Mirapex)

21

Approved in 1997

Bioisostere

Ki D2 = 7 nM D3 = 0.97 nM

Ki D2 = 1 nM D3 = 0.2 nM (agonist)

aminotetralinDual agonist effects at D3 and D2

D3 stimulation may potentiate direct pathwayD2 stimulation may attenuate indirect pathway

D3 is highly expressed in limbic system – some antidepressant effect

Potential antioxidant effect, Oxidation potential ~ 0.32 V vs 0.6 V dopamine water soluble, F = 90%

Journal of the Neurological Sciences 1999, 163, 25.

3/30/11 CHEM E-120

D3 Agonists

22

J. Med. Chem. 2005, 48, 5771-5779

occupation of a1 thought to beimportant for these compounds

a1 not fillednot important?

Ki D3 0.88 nM 5.3 nM 0.2 nM

3/30/11 CHEM E-120

D3 Agonists

233/30/11 CHEM E-120

24

high = ternary complex of ligand, receptor, and G-protein (agonist and antagonist binding)low = (antagonist binding)D2 long = 443 amino acids, postsynapticD2 short = 414 amino acids, presynaptic autoreceptor

3/30/11 CHEM E-120

25SYNAPSE 61:1013–1018 (2007)

3/30/11 CHEM E-120

263/30/11 CHEM E-120

27

J. Med. Chem. 2005, 48, 2493-2508

3/30/11 CHEM E-120

D3 Agonists

28

J. Med. Chem. 2008, 51, 5905

D3 Ki = 0.41 nMD2 330 nM

D1-like 13000 nM

8 compounds

D3 Ki = 0.78 nMD2 3.1 nMD1-like >100K nM

3/30/11 CHEM E-120

29

D3 homology modelβ2 adrenergic

homology modelrhodopsin

3/30/11 CHEM E-120

30

yawning in ratsis a measure ofD3 agonist activity

induction of hypothermiais an indicationof D2 agonist activity

3/30/11 CHEM E-120

31

Therapeutics of Parkinson’s Disease and Other Movement Disorders Edited by Mark Hallett and Werner Poewe © 2008

3/30/11 CHEM E-120

32

The adenosine A2a receptor is a member of the P1 GPCR family that modulates striatal output in the indirect basal ganglia pathway. Inhibition of adenosine A2a receptors produces motor stimulant effects.

Istradefylline (KW-6002) is an orally available, xanthine-based adenosine A2a receptor antagonist (Ki = 2.2 nM) that is in Phase III clinical trials for PD. It has shown positive benefit in reducing the tremor duration and general slowness/stiffness in advanced PD patients.

Adenosine A2a receptor antagonists

Attenuates MPTP-induced loss ofdopaminergic neurons.antioxidant effect?

3/30/11 CHEM E-120

Ki (nM) A2a 2.2 22,000MAO-B 28,000 3.6 mM

O

N

O

S

NNH

NOHO

SYN-115

Synosia – Phase 3

3/30/11 CHEM E-120 33

2011 10.4155/CLI.11.12 © 2011 Future Science Ltd