1. 1 CHEM E-120 Harvard University Extension School Neurodegenerative Disorders Parkinson’s Disease March 30, 2011 3/30/11CHEM E-120

2. 2 Neurodegenerative Diseases Due 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 axons neuroinflammatory 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) 3/30/11CHEM E-120

3. 3 Motor System 1. Corticospinal tract (formally pyramidal system) descends from the motor cortex terminating in the brainstem and spinal cord voluntary movement 2. Basal ganglia tract (formally extrapyramidal system) ascend from midbrain cortex self-initiated movement movement sequencing amplitude and velocity of movement automatic postural and reflex motor activity Basal Ganglia System Anatomically divided into 4 structures: a. striatum: caudate nucleus (cognition), putamen (motor), nucleus accumbens b. globus pallidus c. subthalamic nucleus d. substantia nigra 3/30/11CHEM E-120

4. 4 Thalamus Cortex 3/9/11CHEM E-120 SN SN Substantia nigra - extrapyramidal nigrostriatal pathway GPi internal segment of globus pallidus GPe external segment of globus pallidus striatum GPi GPe excitory inhibitory direct pathway (remove brake) indirect pathway (brake) subthalamic nucleus Movement Control and Basal Ganglia – Normal Conditions GPi and SN tonically active (  movement) dopamine binding to D 1 and D 5 excites direct dopamine binding to D 2, D 3, D 4 inhibits indirect

5. 5 Thalamus Cortex 3/9/11CHEM E-120 SN SN Substantia nigra - extrapyramidal nigrostriatal pathway GPi internal segment of globus pallidus GPe external segment of globus pallidus striatum GPi GPe excitory inhibitory direct pathway (remove brake) indirect pathway (brake) subthalamic nucleus Movement Control and Basal Ganglia – Parkinson’s Disease GPi and SN tonically active (  movement) lack of dopamine binding to D 1 and D 5 inhibits direct lack of dopamine binding to D 2, D 3, D 4 disinhibits indirect reduced

6. 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 toreduce activity direct pathway increase activity indirect pathway disruption of direct/indirect cycles Degeneration of cholinergic, adrenergic, serotonergic systems 3/30/11CHEM E-120

7. 7 Parkinson’s Disease Effects ~ 1% of population with onset most likely at 55-65 years of age Resting tremor of ~ 5 Hz Unilateral or asymmetric onset of bradykinesia (abnormally slow voluntary movements) Rigidity Postural disturbance FRONTLINEFRONTLINE My Father, My Brother, and Me 2009 http://video.mpbn.net/video/1082086931 Onset Motor complications Resistant SymptomsCognitive Decline YEARS 0 8 132025 DEATH 3/30/11CHEM E-120

8. Current Drugs for Parkinson’s 8 3/30/11CHEM E-120

9. 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 3/30/11CHEM E-120

10. Loss of dopamine transporter 10 [ 123 I]-β-CIT DopaScan Nature Reviews Drug Discovery 2006, 5, 845 3/30/11CHEM E-120

11. 12 Parkinsonism caused by MPTP Uptake and accumulation in nigrostriatal dopaminergic neurons. Phase 1 hydrolysisPhase 1 oxidation 3/30/11CHEM E-120 animal treated daily for 7 days with MPTP (30 mg/kg) PNAS 1985, 82, 2173

12. Dopamine Centered Medication Development 12 Loss of dopamine Clinical replacement of dopamine L-DOPA Prevention of dopamine metabolism MAO-B inhibition COMT inhibition Substitution of dopamine D 2 type agonists D 1 type agonists D 3 agonists DAT/Dopamine release Current medications relieve symptoms but do not alter the course of the disease 3/30/11CHEM E-120

13. L-DOPA 13 Currently the medication of choice Prodrug of dopamine, dopamine cannot cross the BBB whereas L-DOPA is transported by aromatic amino acid transporters 3/30/11CHEM E-120

14. 1/28/09CHEM E-12014 Blood-Brain Barrier (BBB) A physical barrier that controls the movement of chemicals f rom 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 membrane glucose amino acids hormones Efflux transporters P-glycoprotein (P-gp) MRP Organic anion transporters (OAT3) Transporters can be on blood side or CNS side of membranes.

15. 1/28/09CHEM E-12015 BBB in Capillary Cell Nature Reviews Drug Discovery 2007, 6, 650

16. 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 inhibitors Sinemet – carbidopa (25mg) and levodopa (100mg) 2-3 times day Clinical Aspects Side effects usually due to peripherally generated dopamine “Wearing off” phenomena Increasing dosage can lead to dyskinesias – excessive and abnormal involuntary movements On/off phenomena Extended release form of Sinemet 3/30/11CHEM E-120

17. 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 3/30/11CHEM E-120

18. 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. 3/30/11CHEM E-120

19. Dopamine Agonists 19 Used alone in early stage Parkinson’s and with L-DOPA in advanced stages StriatumD 1 >> D 5 D 2 > D 3 D 2 antagonists know to produce Parkinson-like effects D 1 partial agonists shown not to be effective D 2 agonists therefore of interest D 3 agonists were found to posses efficacy Efficacy of D 1 activation appears less than D 2 activation making D 1 more susceptible to lower dopamine concentrations Phenotype effects in knockout mice D 1 reduced agonist response, hyperlocomotion D 2 Parkinsonian-like motor impairment D 3 Hyperactivity D 4 reduced locomotion, hypersensitivity to ethanol and stimulants D 5 reduced agonist induced locomotion, startle, and prepulse inhibition 3/30/11CHEM E-120

20. Ergot Akaloids – Dopamine Agonist 20 Bromocriptine (Parlodel) 1967 D 1 -type partial agonist D 2 -type full agonist 5-HT agonist Pergolide (Permax) D 1 -type agonist D 2 -type full agonist 5-HT agonist Cabergoline (Dostinex) Lisuride K i (nM) D1D1 D2D2 D3D3 Dopamine272914669 Bromocriptine1204.930 Cabergoline14621.61.3 Lisuride571.21.1 Pergolide447370.86 3/30/11CHEM E-120

21. D 3 Agonists – Pramipexole (Mirapex) 21 Approved in 1997 Bioisostere K i D 2 = 7 nM D 3 = 0.97 nM K i D 2 = 1 nM D 3 = 0.2 nM (agonist) aminotetralinDual agonist effects at D 3 and D 2 D 3 stimulation may potentiate direct pathway D 2 stimulation may attenuate indirect pathway D 3 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. 3/30/11CHEM E-120

22. D 3 Agonists 22 J. Med. Chem. 2005, 48, 5771-5779 occupation of a 1 thought to be important for these compounds a 1 not filled not important? K i D 3 0.88 nM 5.3 nM 0.2 nM 3/30/11CHEM E-120

23. D 3 Agonists 23 3/30/11CHEM E-120

24. 24 high = ternary complex of ligand, receptor, and G-protein (agonist and antagonist binding) low = (antagonist binding) D 2 long = 443 amino acids, postsynaptic D 2 short = 414 amino acids, presynaptic autoreceptor 3/30/11CHEM E-120

25. 25 SYNAPSE 61:1013–1018 (2007) 3/30/11CHEM E-120

26. 263/30/11CHEM E-120

27. 27 J. Med. Chem. 2005, 48, 2493-2508 3/30/11CHEM E-120

28. D 3 Agonists 28 J. Med. Chem. 2008, 51, 5905 D 3 K i = 0.41 nM D 2 330 nM D 1 -like 13000 nM 8 compounds D 3 K i = 0.78 nM D 2 3.1 nM D 1 -like >100K nM 3/30/11CHEM E-120

29. 29 D 3 homology model β2 adrenergic homology model rhodopsin 3/30/11CHEM E-120

30. 30 yawning in rats is a measure of D 3 agonist activity induction of hypothermia is an indication of D 2 agonist activity 3/30/11CHEM E-120

31. 31 Therapeutics of Parkinson’s Disease and Other Movement Disorders Edited by Mark Hallett and Werner Poewe © 2008 3/30/11CHEM E-120

32. 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 (K i = 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 of dopaminergic neurons. antioxidant effect? 3/30/11CHEM E-120 K i (nM)A2a2.222,000 MAO-B28,0003.6 mM Synosia – Phase 3

33. 3/30/11CHEM E-12033 2011 10.4155/CLI.11.12 © 2011 Future Science Ltd