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Anti -Parkinsonian Drugs-Medicinal Chemistry

Dr.Narmin Hamaamin Husssen

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Anti-Parkinsonian
Drugs
Medicinal Chemistry III / 4th Stage/ 1st Semester
Lecture 3
Dr.Narmin Hamaamin Hussen
2023-2024
m III /
1
Parkinson's Disease
▪ It is a Extrapyramidal motor disorder occurs due to degeneration of CNS dopaminergic
neurons in the substantia nigra result in dopamine deficiency.
▪ Symptoms do not occur until 80% of the neurons in the substantia nigra are lost.
▪ It occur in 2% elderly population.
2
Causes
▪ Parkinson is caused due to imbalance of dopamine (inhibitory neuron)and
acetylcholine(excitatory cholinergic neuron).
▪ Dopamine and acetylcholine need to be balanced for smooth movement. DA causes muscle
relaxation while Ach causes contraction.
▪ Reduction of DA, in the substantia nigra results in imbalance of those two and causes motor
disorders.
3
4
Dopaminergic pathways
Accounts for ~75%
of the DA in the brain
5
Lack of Dopamine
Symptoms
Synthesis of Dopamine
6
Tyrosine
hydroxylase
L-aromatic
amino acid
decarboxylase
▪ DA is classified as a catecholamine neurotransmitter based on its catechol nucleus and is derived from the
amino acid tyrosine
▪ Tyrosine is transported across the blood-brain barrier (BBB) into the brain, where it is then taken up by
dopaminergic neurons.
▪ Once L-tyrosine enters the dopaminergic neuron, it is converted to L-dihydroxyphenylalanine (L-DOPA) by
the enzyme tyrosine hydroxylase (TH), which is the rate-limiting step in DA synthesis.
▪ Subsequently, the enzyme L-aromatic amino acid decarboxylase (AADC) converts LDOPA to DA. The normally
high levels of AADC in the brain will allow for the substantial increase in DA levels if levels of L-DOPA are
increased.
▪ DA itself does not cross the BBB; however, L-DOPA crosses via the large neutral amino acid carrier.

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Anti -Parkinsonian Drugs-Medicinal Chemistry

  • 1. Anti-Parkinsonian Drugs Medicinal Chemistry III / 4th Stage/ 1st Semester Lecture 3 Dr.Narmin Hamaamin Hussen 2023-2024 m III / 1
  • 2. Parkinson's Disease ▪ It is a Extrapyramidal motor disorder occurs due to degeneration of CNS dopaminergic neurons in the substantia nigra result in dopamine deficiency. ▪ Symptoms do not occur until 80% of the neurons in the substantia nigra are lost. ▪ It occur in 2% elderly population. 2
  • 3. Causes ▪ Parkinson is caused due to imbalance of dopamine (inhibitory neuron)and acetylcholine(excitatory cholinergic neuron). ▪ Dopamine and acetylcholine need to be balanced for smooth movement. DA causes muscle relaxation while Ach causes contraction. ▪ Reduction of DA, in the substantia nigra results in imbalance of those two and causes motor disorders. 3
  • 4. 4 Dopaminergic pathways Accounts for ~75% of the DA in the brain
  • 6. Synthesis of Dopamine 6 Tyrosine hydroxylase L-aromatic amino acid decarboxylase ▪ DA is classified as a catecholamine neurotransmitter based on its catechol nucleus and is derived from the amino acid tyrosine ▪ Tyrosine is transported across the blood-brain barrier (BBB) into the brain, where it is then taken up by dopaminergic neurons. ▪ Once L-tyrosine enters the dopaminergic neuron, it is converted to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH), which is the rate-limiting step in DA synthesis. ▪ Subsequently, the enzyme L-aromatic amino acid decarboxylase (AADC) converts LDOPA to DA. The normally high levels of AADC in the brain will allow for the substantial increase in DA levels if levels of L-DOPA are increased. ▪ DA itself does not cross the BBB; however, L-DOPA crosses via the large neutral amino acid carrier.
  • 7. Dopamine Metabolism • DA metabolism occurs through enzymatic action; via monoamine oxidase (MAO) or catechol-O- methyltransferase (COMT) . • DA can be converted to either dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA). • In humans, the major brain metabolite is HVA, followed by DOPAC. 7
  • 8. Classification of Anti-Parkinsonian Drugs 8 1. Drugs affecting brain dopamine a. Drugs that increase brain levels of dopamine(Dopamine precursors )(Levodopa) b. Drugs that decrease dopamine metabolism(Peripheral decarboxylase inhibitors )(carbidopa) c. Dopamine releasers(Dopamine facilitator ) (Amantadine) d. Dopamine receptor stimulation: Dopaminergic agonists(Bromocriptine) e. Selective MAO-B Inhibitor(Selegiline, Rasagiline, Safinamide) f. COMT Inhibitors (Entacapone, Tolcapone, Opicapone) 2. Anticholinergic agents a. Piperidine analogues b. Pyrrolidine analogues c. Phenothiazine analogues ▪ The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors. ▪ D1 receptor stimulation may also be required for maximal benefit. ▪ Antiparkinsonism properties have dopamine agonists and partial agonist ergot derivatives (lergotrile, bromocriptine), both stimulators of D2 receptors. ▪ Dopamine antagonists can induce parkinsonism
  • 9. Drugs affecting brain dopamine 9 Periphery BBB
  • 10. Dopamine is not used for parkinsondisease therapy,why? ▪ Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. Because its freely soluble in water, methanol, and hot 95%ethanol. ▪ Levodopa or (-)-3-(3,4-dihydroxyphenyl)-L-alanine is the immediate metabolic precursor of dopamine. ▪ Levodopa enters the brain via an L-amino acid transporter (LAT), where it is decarboxylated to dopamine
  • 11. ➢ Levodopa: ▪ Levodopa is essentially a prodrug; that is itself inactive, but after penetrating, the BBB is metabolized to DA. ▪ Levodopa is indicated for the treatment of idiopathic, postencephalitic, and symptomatic Parkinsonism. ▪ Levodopa is rapidly absorbed from the small intestine by an active transport system for aromatic amino acids. It is widely distributed to most body tissues, but less to the CNS, and is bound to plasmaproteins only to aminor extent (10%–30%). ▪ Drugs that increase brain levels of dopamine(Dopamine precursors )
  • 12. ▪ Levodopa is extensively decarboxylated by first-pass metabolism in the liver. ▪ A small amount is methylated to 3-O-methyldopa (3OMD), which accumulates in the CNS because of its long half-life. ▪ Most of levodopa is converted to DA, small amounts of which in turn are metabolized to norepinephrine and epinephrine. ▪ At least 30 metabolites of levodopa have been identified. Metabolites of DA are rapidly excreted in the urine. ▪ The principal metabolites DOPAC and HVA .After prolonged therapy with levodopa, the ratio of DOPAC and HVA excreted may increase, probably reflecting a depletion of methyl donors necessary for metabolism by COMT. ▪ Oral administration of levodopa alone results in the rapid peripheral conversion of levodopa to dopamine which decreases the desired therapeutic effect and causes significant GI side effects such as nausea and vomiting. 12
  • 15. ➢ Levodopa/Carbidopa (sinemet): ▪ Sinemet®is acombination ofcarbidopaandlevodopafor thetreatmentofParkinson's disease and syndrome. ▪ Coadministration of levodopa with the AADC inhibitor, carbidopa, prevents decarboxylation of levodopa outside of the CNS. ▪ The combination of levodopa and carbidopa results in a substantial increase in DA delivery to the CNS with a decrease in peripheralside effects. ▪ Carbidopa does not cross theblood-brain barrier. ▪ Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain.The addition of carbidopa allows lower doses of levodopa to be used. Peripheral decarboxylase inhibitors (aromatic L-amino acid decarboxylase inhibitor AADC)
  • 16. ➢Benserazide: ▪ Benserazide is aperipherallyactingaromatic L-amino aciddecarboxylase or DOPA decarboxylase inhibitor,whichis unableto cross theblood–brain barrier. ▪ The primary therapeutic use for which benserazide is currently indicated for is as a combination therapy with levodopa for the treatment of Parkinson's disease in adults > 25 years of age, with th exception of drug-induced parkinsonism
  • 17. ➢ Amantadine: ▪ Indications:Treatment of symptoms of Parkinson's disease by improving muscle control and reducing stiffness, shakinessandshuffling. ▪ Amantadinetreats parkinsonian dyskinesiaasamuscarinicantagonistandactsas anoncompetitive NMDA antagonist. ▪ Amantadinewas usedasanantiviraldrug to treatandpreventinfluenzaA infections. ▪ In 2017,theU.S.Food andDrug Administration approved theuseofamantadineinanextended releaseformulationdevelopedbyAdamas Pharmaforthetreatmentofdyskinesia,anadverse effectof levodopa,that peoplewithParkinson's experience Dopamine releasers(Dopamine facilitator )
  • 18. Dopamine receptor stimulation: Dopaminergic agonists ▪ Bromocriptine acts as an agonist at D2-like receptors and an antagonist at D1- like receptors. ▪ Bromocriptine is used in the treatment of acromegaly, pituitary tumors, Parkinson’s disease (PD) and hyperprolactinaemia. ▪ Lisuride is a semisynthetic ergoline and potent central dopamine, that is useful in the management of patients in an advanced stage of parkinsonism where levodopa therapy is no longer sufficient . ▪ DA agonists are classified into ergot derivatives ( bromocriptine , Lisuride and cabergoline) and nonergot derivatives (apomorphine, pramipexole, ropinirole, and rotigotine).
  • 19. ➢ Cabergoline(Dostinex ): ▪ CabergolineexhibitshighaffinityatD2-like receptors withover 50-foldselectivitycompared withD1-like receptor. ▪ Cabergolineis a potent D2 receptor agonist and is indicated for the treatmentofhyperprolactinemic disorders, eitheridiopathicor causedbypituitary adenomas.
  • 21. ▪ MAO inhibitors areutilizedto prolong theplasmahalf-lifeoflevodopa or block the striatalmetabolismof DA. ➢Selegiline ▪ Selegilineis anirreversible MAO-B inhibitor. ▪ Selegiline potentiates the effects of levodopa by blocking its metabolism by MAO. When administeredwith levodopa,selegilineallowsfor areduction inthedaily dosage. ▪ Selegilineis readily absorbed from theGI tract.It is well distributed in the body andit penetratesthe CNS. Selegiline has a high apparent volume of distribution, short half-life, and a very high oral clearance, indicating an extensive metabolism not only in the liver but also through extrahepatic biotransformation. MAO-B Inhibitors:
  • 23. ➢Rasagiline Mesylate: ▪ Rasagilineis aselectiveirreversible inhibitor of MAO-B thatis approximatelyfivetimesmore potent than selegiline. ▪ Rasagiline is rapidly absorbed.It undergoes complete biotransformation before excretion,mainly via N-dealkylationandhydroxylation, to yieldthreemajormetabolites:1(R)-aminoindan,3-hydroxy-N- propargyl-1-aminoindan, and3- hydroxy-1-aminoindan.
  • 24. 24 ➢ Safinamide ▪ Safinamide is a drug used as an add-on treatment for Parkinson's disease with "off" episodes. when levodopa stops working. ▪ it has multiple modes of action, including the inhibition of monoamine oxidase B. ▪ It was approved in the European Union in February 2015, in the United States in March 2017,and in Canada in January 2019. ▪ What is the ON/OFF phenomenon in Parkinson’s? ▪ During an ON episode, the levodopa is working well and symptoms improve. ▪ During an OFF episode, the levodopa isn’t working and symptoms return or get worse
  • 25. ▪ When administered with anAADC inhibitor, circulating levodopa is mainly metabolized by COMT. In thepresence of aCOMT inhibitor, theperipheralmetabolism oflevodopais therefore decreased. ➢ Tolcapone: ▪ Tolcapone is a selective and reversible inhibitor of COMT in the CNS and periphery. Inhibition of COMT in the periphery reduces the formation of3OMD intissuesthathavesignificant COMT activity. ▪ Administration of levodopa in combination with adopa decarboxylase inhibitor (carbidopa) and aCOMT inhibitor(tolcapone) increasesCNS deliveryoflevodopa. COMT Inhibitors:
  • 26. ➢ Entacapone: ▪ Entacapone is rapidly absorbed afteroral administration and does not cross the BBB. ▪ Entacaponedoes not distribute widelyinto tissuesbecauseofitshighplasmaprotein bindinganditiscompletelymetabolizedbefore excretion ▪ Unlike tolcapone,entacaponedoes not penetrate theBBB to any extent.Thus,the compound onlyinhibits peripheralCOMT. ▪ When combined with levodopa and carbidopa, entacapone provides less motor fluctuations and plasmalevelsof levodopa are greater and more sustained inparkinsonian patients. ▪ Another advantage of entacaponeover tolcapone is its lackof hepatotoxicity.
  • 27. 27 ➢ Opicapone ▪ The COMT inhibitor opicapone is used as an additive to a combination of levodopa and a DOPA decarboxylase inhibitor to treat patients with Parkinson's disease experiencing end-of-dose motor fluctuations, if they cannot be stabilised with this drug combination("off" episodes). ▪ In June 2016, it was authorised for use in the European Union. It was authorised for use in the United States in April 2020
  • 28. 28 2- Anticholinergic agents ➢ Piperidine analogues ➢ Biperiden is used alone or together with other medicines (e.g., levodopa) to treat Parkinson's disease. By improving muscle control and reducing stiffness, this medicine allows more normal movements of the body as the disease symptoms are reduced. ➢ Cycrimine is a drug used to reduce levels of acetylcholine to return a balance with dopamine in the treatment and management of Parkinson's disease.
  • 29. 29 ➢ Pyrrolidine analogues ➢ Procyclidine HCl ▪ Procyclidine belongs to a class of medication called anticholinergics that work by blocking a certain natural substance (acetylcholine). This helps decrease muscle stiffness, sweating, and the production of saliva, and helps improve walking ability in people with Parkinson's disease. ▪ Anticholinergics can stop severe muscle spasms of the back, neck, and eyes that are sometimes caused by psychiatric drugs(antipsychotics such as chlorpromazine/haloperidol)
  • 30. 30 ➢ Phenothiazine analogues ➢ Ethopropazine HCl(Profenamine ) ▪ Profenamine is a phenothiazine derivative used as an antiparkinsonian agent that has anticholinergic, antihistamine, and antiadrenergic actions. ▪ It is also used in the alleviation of the extrapyramidal syndrome induced by drugs such as other phenothiazine compounds, but, like other compounds with antimuscarinic properties, is of no value against tardive dyskinesia.
  • 31. ➢Istradefylline (Nourianz ): ▪ Istradefyllineis amedicationusedto treatParkinson's disease (PD). ▪ Istradefyllinereduces"off" periods resulting fromlong-termtreatmentwiththeantiparkinson drug levodopa. ▪ An "off" episodeis atimewhenapatient'smedications arenot working well,causingan increaseinPD symptoms, such astremor anddifficulty walking. ▪ It is aselectiveantagonist attheA2A receptor.Itwasfirst approvedinJapanin2013.Itwas approved bytheFood andDrug Administration (FDA) intheUnited Statesin 2019. Newer Drugs:
  • 32. ➢ Pimavanserin(Nuplazid): ▪ Pimavanserin is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis and is also being researched for the treatment of Alzheimer’s disease psychosis, schizophrenia, agitation, and major depressive disorder. ▪ On April 29, 2016 Nuplazid (pimavanserin) was approved by the FDA for the treatment of hallucinations and delusions associated withParkinson’s disease psychosis. ▪ Unlike other antipsychotics,pimavanserinis not adopamine receptor antagonist. ▪ Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist oftheserotonin 5-HT2A receptor.
  • 33. What is deep brain stimulation? 33 https://youtu.be/kWAVOhl9OFk
  • 34. Deep brain stimulation 34 ▪ Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleus) for the treatment of movement disorders, including Parkinson's disease, essential tremor, and dystonia. ▪ DBS has been approved by the Food and Drug Administration as a treatment for essential tremor and Parkinson's disease (PD) since 1997. ▪ DBS was approved for dystonia in 2003,obsessive–compulsive disorder (OCD) in 2009, and epilepsy in 2018 ▪ DBS is used to manage some of the symptoms of Parkinson's disease that cannot be adequately controlled with medications. ▪ PD is treated by applying high-frequency (> 100 Hz) stimulation to three target structures, namely to the ventrolateral thalamus, internal pallidum, and subthalamic nucleus (STN) to mimic the clinical effects of lesioning. ▪ It is recommended for people who have PD with motor fluctuations and tremors inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems.
  • 35. Parkinson's Disease Biomarker Found 1. Alpha-synuclein ▪ Researchers have discovered a new tool that can reveal a key pathology of the disease: abnormal alpha-synuclein known as the “Parkinson’s protein” in brain and body cells. ▪ The tool, called the α-synuclein seeding amplification assay (αSyn-SAA), can detect pathology in spinal fluid not only of people diagnosed with Parkinson’s, but also in individuals who have not yet been diagnosed or shown clinical symptoms of the disease, but are at a high risk of developing it. 35 2. DOPA decarboxylase DOPA decarboxylase is an emerging biomarker for Parkinsonian disorders including preclinical Lewy body disease(https://doi.org/10.1038/s43587-023-00478-y)
  • 36. 36