Parkinson's Disease Agents PDF

L-Dopa L-Dopa is an amino acid that has been used as dopamine replacement therapy since it is capable of crossing the bloodbrain barrier and undergoing decarboxylation to generate dopamine in the brain. However, L-Dopa is currently coadministered/coformulated with a DOPA decarboxylase inhibitor (e.g...

L-Dopa L-Dopa is an amino acid that has been used as dopamine replacement therapy since it is capable of crossing the bloodbrain barrier and undergoing decarboxylation to generate dopamine in the brain. However, L-Dopa is currently coadministered/coformulated with a DOPA decarboxylase inhibitor (e.g., carbidopa or benserazide). Pharmacokinetics of drugs used to treat Parkinson’s disease are next slide. 20 21 Carbidopa Carbidopa is used in combination with L-Dopa for the treatment of Parkinson’s disease. The amine in L-Dopa has been replaced with a hydrazine moiety, while the absolute stereochemistry (e.g., S) has been retained. The carbon that the hydrazine is attached to is further substituted with a methyl group. The hydrazine that can readily react with a cofactor in the active site of L-Dopa decarboxylase. 22 Benserazide is another L-Dopa decarboxylase inhibitor. It is comprised of the racemic form of the amino acid serine linked through an acyl hydrazine, which is further substituted with pyrogallol attached through a methylene. Benserazide is readily hydrolyzed in plasma to trihydroxybenzylhydrazine that readily reacts with a cofactor in the active site of L-Dopa decarboxylase. Carbidopa does not cross the blood-brain barrier, it does not affect the metabolism of L-Dopa within the central nervous system. However, carbidopa reduces the amount of L-Dopa required for therapeutic response by about 75% by increasing both the plasma level and half-life of L-Dopa, and decreasing plasma and urinary dopamine and homovanillic acid levels. 23 A cocrystal structure (next slide) of a carbidopa derivative containing a hydrazone linkage to its cofactor pyridoxal-5′phosphate (PLP) bound to L-Dopa decarboxylase has been reported. The structure reveals: - a hydrogen bond and an ionic-dipole interaction between the catechol and the alcohol side-chain of Thr82 (e.g., threonine residue 82) and the phosphate of PLP, respectively, and - interactions between the carboxylate of carbidopa and the imidazole side-chain of His192. A cocrystal structure of benserazide with DOPA decarboxylase has not been reported. 24 Cocrystal structure of carbidopa-pyridoxal-5′-phosphate (PLP) hydrazone with L-Dopa decarboxylase (PDB: 1JS3). Hydrogen bonding interactions shown with red dashes. 25 About 30% of a carbidopa dose is eliminated unchanged in urine. Carbidopa is metabolized to generate α-methyl-3,4dihydroxyphenylpropionic acid (Figure slide 28) via reduction of the hydrazine. This metabolite is converted to α-methyl-3methoxy-4-hydroxyphenylpropionic acid, presumably by catechol-O-methyltransferase. The catechol metabolite also undergoes a reduction to α-methyl-3-hydroxyphenylpropionic acid. 26 All three of these metabolites participate in conjugation with glucuronic acid with subsequent elimination in urine (structures of the glucuronides have not been reported). Finally, 3,4- dihydroxyphenylacetone has also been isolated from urine after administration of carbidopa. This compound may arise via oxidative decarboxylation of α-methyl-3-methoxy-4 hydroxyphenylpropionic acid. It may also form directly by autooxidation of the parent drug. 27 Metabolism of carbidopa. 28 Several drug-drug interactions can occur with carbidopa : - iron salts (including in multivitamins) can chelate carbidopa reducing its bioavailability. - carbidopa can have a drug-drug interaction with isoniazid (antibiotic used for the treatment of tuberculosis) since both inhibit tryptophan oxygenase and kynureninase. The most common adverse reactions in early Parkinson’s disease patients are nausea, dizziness, headache, insomnia, abnormal dreams, dry mouth, dyskinesia, anxiety, constipation, vomiting, and orthostatic hypotension. In advanced Parkinson’s disease patients the most common adverse events include nausea and headache. 29 Monoamine Oxidase Inhibitors Rasagiline, selegiline, and safinamide block the conversion of dopamine to 3,4-dihydroxyphenylacetaldehyde via inhibition of the enzyme monoamine oxidase. R L-deprenyl 30 Rasagiline Rasagiline is indicated as a monotherapy or as adjunct therapy in Parkinson’s disease patients taking L-Dopa. Rasagiline acts as a selective inhibitor of monoamine oxidase B. Rasagiline does not block the enzyme activity by reversibly binding to the active site. Instead, it is initially a substrate for monoamine oxidase B and is converted to a reactive intermediate that then forms a covalent irreversible adduct with the enzyme cofactor FAD (Figure next slide B). Monoamine oxidase B oxidation activates the propargyl amine to undergo nucleophilic attack by one of the N atoms of FAD. The resulting adduct of this reaction can be seen in a reported rasagiline·monoamine oxidase B·FAD cocrystal structure (Figure next slide B). 31 (A) Covalent interaction between rasagiline, monoamine oxidase-B, and flavin adenine dinucleotide (FAD). (B) Cocrystal structure of rasagiline covalently bonded to flavin adenine dinucleotide (FAD) and complexed with monoamine oxidase-B (PDB: 1S2Q). 32 Rasagiline is highly metabolized and undergoes almost complete biotransformation in the liver prior to excretion. The parent drug is N-dealkylated to yield 1-aminoindane (Fig. next slide). It also undergoes benzylic oxidation to form 3-hydroxy-N-propargyl-1- aminoindane. Both of these metabolites can be further oxidized to 3-hydroxy-1-aminoindane. All of these metabolic reactions are CYP450 mediated, with CYP1A2 being the major isoenzyme involved. These phase 1 metabolites also undergo glucuronidation before subsequent urinary excretion. The most common adverse effects of rasagiline are somnolence, hypotension, dyskinesia, psychotic-like behavior, compulsive behaviors, withdrawal-emergent hyperpyrexia (high fever; greater than 41C), and confusion. 33 Phase 1 metabolism of rasagiline. 34 Selegiline Selegiline is approved as an adjunct therapy in the management of parkinsonian patients being treated with L-Dopa/carbidopa who exhibit deterioration in the quality of their response to dopamine replacement therapy. Selegiline has not demonstrated beneficial effect in the absence of concurrent L-Dopa/carbidopa therapy. Selegiline is structurally related to rasagiline, except that it contains a tertiary amine and a 2-phenylpropyl in place of the indane. Similar to rasagiline, selegiline is a substrate for monoamine oxidase-B oxidation and subsequent reactivity with FAD to form a covalent adduct. Hence, it is a selective irreversible inhibitor of monoamine oxidase-B. 35 Selegiline undergoes extensive metabolism to (R)- methamphetamine, via oxidative dealkylation of the propargyl, as the major plasma metabolite (Fig. next slide). A minor metabolite is N-desmethylselegiline, which is also an irreversible monoamine oxidase-B inhibitor that is not surprising given its structural similarity to both selegiline and rasagiline. N-Desmethylselegiline is further metabolized to (R)-amphetamine again via oxidative dealkylation of the propargyl. Both (R)-methamphetamine and (R)amphetamine undergo aromatic hydroxymethamphetamine and hydroxylation to (R)-4- (R)-4-hydroxyamphetamine, respectively, which are found as their corresponding glucuronide phase II metabolites in urine. 36 Metabolism of selegiline. 37 Selegiline is contraindicated for use with meperidine and other opioids due to increased risk of serotonin syndrome. Central nervous system toxicity can occur with the combination of : - tricyclic antidepressants and selegiline. - selegiline and selective serotonin reuptake inhibitors. The most common adverse effects of selegiline include nausea, hallucinations, confusion, depression, loss of balance, insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia, slowness of movement, chorea, delusions, hypertension, new or increased angina pectoris, and syncope. 38 Safinamide Safinamide is approved as an adjunct therapy to L- Dopa/carbidopa and has resulted in improved motor function without involuntary movements. The drug has not been shown to be effective as a monotherapy for Parkinson’s disease. Safinamide is a reversible monoamine oxidase-B inhibitor and does not form a covalent bond with the enzyme or the FAD cofactor. The mode of inhibition still results in increased levels of dopamine. It has 5000-fold selectivity over inhibition of monoamine oxidase-A. 39 Several molecular interactions contribute to the binding of safinamide to monoamine oxidase-B, which occur close to the bound FAD. These engagements include van der Waal interaction of the 3-fluorobenzyloxy moiety and hydrogen bonding of the amide and secondary amine of safinamide with Gln206 and an ordered water molecule (Fig. next slide). Safinamide also inhibits glutamate release and dopamine reuptake, as well as blocks Na+ and Ca2+ channels. However, these latter two properties probably do not contribute to the drug’s pharmacodynamic effects in the treatment of Parkinson’s disease. 40 Cocrystal structure of safinamide with monoamine oxidase-B and flavin adenine dinucleotide (FAD) (PDB: 2V5Z). Hydrogen bonding interactions are depicted with red dashes. 41 Although safinamide avoids first pass metabolism, it does eventually undergo extensive metabolism with only about 8.5% of the parent drug being excreted unchanged in urine and feces. Safinamide undergoes amidase-mediated hydrolysis of the primary amide to the corresponding carboxylic acid, which is Ndealkylated to a primary amine (Fig. next slide). Alternatively, the parent drug is directly N-dealkylated to generate the same primary amine. This metabolite is deaminated via monoamine oxidase-A oxidation to the corresponding aldehyde, which is oxidized via aldehyde dehydrogenase to the carboxylic acid, which is the primary metabolite found in plasma. In addition, this metabolite undergoes phase 2 UGT-mediated glucuronidation. 42 Metabolism of safinamide. 43 The metabolites of safinamide are primarily excreted via the kidney. None of these metabolites appear to exhibit biological activity responsible for the pharmacodynamic effects of the parent drug in the treatment of Parkinson’s disease. Animal and human studies have not revealed an increased risk of drug-drug interaction with safinamide. However, individuals with severe liver dextromethorphan problems (cough as well suppressant), as other those using monoamine oxidase inhibitors, opioids, St. John’s wort, antidepressants, or cyclobenzaprine (muscle relaxer) should not use safinamide. The most common adverse effects of safinamide include uncontrolled involuntary movements, nausea, insomnia, and falls. 44 Catechol-O-Methyltransferase Inhibitors Entacapone and tolcapone block the conversion of dopamine to 3methoxytyramine by inhibition of the enzyme catechol-O- methyltransferase. E 45 Entacapone Entacapone is approved for the treatment of Parkinson’s disease as an adjunct therapy to L-Dopa/carbidopa. Entacapone is significantly metabolized prior to excretion, with only 0.2% of the parent drug found unchanged in urine and 10% in feces. It undergoes alkene isomerization to the inactive Z-isomer. (Z)-entacapone is the only phase 1 metabolite found in human plasma. The parent drug is metabolized via glucuronidation predominately by UGT1A9 to generate two regioisomeric metabolites. The isomerized phase 1 metabolite also undergoes glucuronidation. 46 The resulting glucuronides from the parent and the alkene isomer represent about 70% and 25%, respectively, of the urinary metabolites (Fig. next slide). The nitro group appears to block catechol-O-methyltransferase-mediated methylation of the catechol. The most common adverse effects of entacapone are urine discoloration, nausea, hyperkinesia, abdominal pain, vomiting, and dry mouth. 47 Metabolism of entacapone. 48 Tolcapone Tolcapone is indicated for the treatment of Parkinson’s disease as an adjunct therapy to L-Dopa/carbidopa. Tolcapone is a selective and reversible inhibitor of catechol-Omethyltransferase. As can be seen in the tolcapone·S-adenosyl methionine·catechol-O-methyltransferase·Mg2+ cocrystal structure, the catechol of tolcapone forms an interaction with the Mg2+ ion as well as a hydrogen bond to Asn170 and an ionic-dipole interaction with Glu199 (Fig. next slide). The S-adenosylmethionine methyl group that normally is transferable to the substrate is positioned close to the para-hydroxyl group of tolcapone. Transfer does not occur likely due to the strong electron-withdrawing effect of the nitro group, although some methylation of the other hydroxyl group is observed as a minor metabolite. 49 Tolcapone·S-adenosyl methionine (SAM)·catechol-O-methyltransferase (COMT)·Mg2+ cocrystal structure (PDB: 3S68). Hydrogen bonding interactions are shown with red dashes. The transferable methyl on SAM is highlighted with a red dashed circle. Residues 3-12 and 21-56 have been deleted for clarity. 50 Tolcapone is extensively metabolized prior to excretion, with only 0.5% of the dose found unchanged in urine and 60% and 40% of the metabolites excreted in urine and feces, respectively. The primary metabolite of tolcapone is the glucuronide of the more sterically accessible phenol (Fig. next slide). Several minor metabolites are also formed, including oxidation of the benzylic position (via CYP3A4 and 2A6) to an alcohol that is subsequently oxidized to the corresponding carboxylic acid, reduction of the nitro to an aniline that is subsequently acetylated, and catechol-O-methyltransferase-mediated methylation to 3-Omethyl-tolcapone. The most common adverse effects of tolcapone are nausea, anorexia, sleep disorder, vomiting, urine discoloration, dystonia (uncontrolable muscle contraction), and sweating. 51 Tolcapone glucuronide Metabolism of tolcapone. 52 Dopamine Receptor Agonists Another strategy for the treatment of Parkinson’s disease is through agonism of dopamine receptors, particularly postsynaptic D2-types. Apomorphine, bromocriptine, carbergoline, pramipexole, ropinirole, and rotigotine, work via this mode, providing symptomatic relief to Parkinson’s disease patients. R S S 53 Apomorphine Apomorphine is indicated for the acute, intermittent treatment of hypomobility, or “off” episodes (e.g., times when other Parkinson’s disease medications, such as L-dopa/carbidopa, are not working well) in patients with advanced Parkinson’s disease. It is a synthetic compound related to a class of alkaloids called aporphines that are found in a wide variety of plants. Apomorphine’s mechanism of action in the treatment of Parkinson’s disease is postulated to occur via stimulation of postsynaptic dopamine D2-type receptors within the caudateputamen or corpus striatum region of the brain. 54 The rigid tetracyclic structure and OH groups at C10 and C11 of (R)-apomorphine mimic the trans-α-conformational isomer of dopamine (Fig. next slide) likely representing the binding conformation. (R)-isoapomorphine that displays the structure of dopamine in the trans-β-conformational isomer has less activity. (R)-1,2-dihydroxyaporphine that displays the structure of dopamine in the cis-α-conformational isomer is inactive as a dopamine receptor agonist. The most common adverse effects of apomorphine are nausea and vomiting, coronary events, QT prolongation, proarrhythmia (provocation of a new arrhythmia or the aggravation of a preexisting one during therapy), and priapism (prolonged erection of the penis). 55 Less active Comparison of conformational restricted dopamine analogues (R)apomorphine, (R)isoapomorphine, and (R)1,2-dihydroxyaporphine with the trans-α-, trans-β-, and cis-α-conformational isomers of dopamine. Inactive 56 Bromocriptine Bromocriptine is indicated for the treatment of idiopathic or postencephalitic Parkinson’s disease, as well as hyperprolactinemia (high levels of the hormone prolactin which stimulates breast milk production during and after pregnancy in the blood)-associated dysfunctions and acromegaly (disorder that results in excess growth of certain parts of the human body). It is a structurally complex synthetic compound related to naturally occurring ergot alkaloids. Bromocriptine is a partial agonist at D2 and D3 receptors with selective over D1, D4, and D5 receptors. 57 The drug undergoes extensive first pass metabolism with the main route of elimination in bile (80%-93% of the absorbed dose) with little parent drug excreted in urine and feces. Two primary pathways are responsible for metabolism of bromocriptine: 1) hydrolysis and epimerization generating 2-bromolysergic acid and the epimer 2-bromoisolysergic acid via the intermediate amides (Fig. next slide). 2) oxidation of C8 in the Pro fragment. Further oxidation of the C9 position, as well as formation of the 8-O- and 9-O-glucuronides, occurs. These metabolites are likely also susceptible to hydrolysis and epimerization. The lysergic acid portion of bromocriptine and its metabolites seems quite stable to metabolism. 58 Path 1 Path 2 59 Metabolism of bromocriptine. The most common adverse effects of bromocriptine with concomitant reduction in the dose of L-dopa/carbidopa are nausea, confusion, abnormal “on-off’’ involuntary movements, phenomenon, dizziness, hallucinations, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo. 60 Cabergoline Cabergoline is indicated for the treatment of early phase Parkinson’s disease, and hyperprolactinemic disorders (e.g., idiopathic or due to pituitary adenomas). Its mechanism of action is also similar to bromocriptine, demonstrating full agonism at D2 receptors and partial agonism at D3 and D4 receptors, without appreciable activity at D1 receptors. The drug is extensively metabolized by the liver, with fecal excretion of metabolites as the main route of elimination over a prolonged period of time. 61 Two hydrolysis routes of the acylurea account for the predominate metabolism of cabergoline (Fig. next slide): 1) the urea moiety is hydrolyzed to generate a secondary amide. 2) the acylurea bond is broken to produce the carboxylic acid. But, similar to bromocriptine, the tetracyclic scaffold is quite resistant to metabolism. The drug’s most common adverse effects are headache, nausea, and vomiting. 62 Path 1 Path 2 Metabolism of cabergoline. 63 Pramipexole Pramipexole is indicated for the treatment of Parkinson’s disease. Mechanistically, it is a D2 receptor agonist with affinity for the D3 and D4 receptor subtypes, but low affinity for the D1 receptor. Pramipexole is not extensively metabolized, contributing to a long terminal plasma elimination half-life of 8-12 hours, with 90% excreted in urine unchanged with clearance of 400 mL/min. Pramipexole does not significantly inhibit CYP450 enzymes and does not appear to participate in drug-drug interactions. The most common adverse effects of pramipexole are nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations. 64 Ropinirole Ropinirole is a D2 agonist with weaker binding affinities to D3, D4, 5-HT2 (5-hydroxytryptamine 2), and α2 receptors. The primary route of elimination is in urine with