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Tyrosine
Tyrosine is converted to LDOPA by the action of an enzyme called aromatic hydroxylase
LDOPA
LDOPA is converted to Dopamine by the action of DOPA decarboxylase
DOPA is an abbreviation of DiOxyPhenylAlanine
LDOPA is a prodrug that must undergo metabolism into the required hormone DA
Dopamine
D2 receptors are the receptors that most associted with Parkinson’s condition. Shortage of DA specially at D2 receptors results in Parkinson’s symptoms
Carbidopa
*Notice that carbidopa differs from LDOPA in two functional groups: a hydrazine (-NH-NH2) in place of the amino, and an alpha methyl group to the hydrazino group.
Bromocriptine
Natural DA direct agonists: Ergot alkaloids
*Ergot is a plant that produces several types of alkaloids (an alkaloid is a naturally synthesized organic molecule with basic nitrogen)
All have ring system composed of three rings fused together: indole, cyclohexane and piperidine ring systems.
the bridge (spacer) between the benzene ring of indole and the basic nitrogen in the pyridine mimics the phenyl-ethylamine backbone of DA (that may explain the direct agonist activity at D-2 receptors).
Both drugs have direct dopaminergic agonist activities at the D-2 receptors hence, its values in Parkinson’s condition.
What you should focus in the structural differences between the two alkaloids is: Bromocriptine has N-CH3 group and Pergolide has S-CH3 group. Both drugs are metabolized by removing the methyl group from Bromocriptine to give active metabolite; while removal of the CH3 rom the sulfur gives inactive metabolite. N demethylation
That explains why bromocriptine is given once a day and Pergolide is given twice a day. *The total dose of bromocriptine is 40 mg/day, while the total dose of Pergolide is 3 mg/day. For that higher potency and lower dose; Pergolide is more commonly used than Bromocriptine in the treatment of Parkinson’s.
Pergolide
Natural DA direct agonists: Ergot alkaloids
Ergot is a plant that produces several types of alkaloids (an alkaloid is a naturally synthesized organic molecule with basic nitrogen)
All have ring system composed of three rings fused together: indole, cyclohexane and piperidine ring systems.
the bridge (spacer) between the benzene ring of indole and the basic nitrogen in the pyridine mimics the phenyl-ethylamine backbone of DA (that may explain the direct agonist activity at D-2 receptors).
Both drugs have direct dopaminergic agonist activities at the D-2 receptors hence, its values in Parkinson’s condition.
What you should focus in the structural differences between the two alkaloids is: Bromocriptine has N-CH3 group and Pergolide has S-CH3 group. Both drugs are metabolized by removing the methyl group from Bromocriptine to give active metabolite; while removal of the CH3 rom the sulfur gives inactive metabolite. S demethylation
That explains why bromocriptine is given once a day and Pergolide is given twice a day. *The total dose of bromocriptine is 40 mg/day, while the total dose of Pergolide is 3 mg/day. For that higher potency and lower dose; Pergolide is more commonly used than Bromocriptine in the treatment of Parkinson’s.
Ropinirole (Requip®)
Synthetic Direct Dopaminergic Agonists
All three drugs are acting as direct dopaminergic agonists at D-2 receptors (they are not prodrugs). All three drugs have common structural features close to the phenyl-ethylamine backbone. All three drugs are used in mg and sub-mg doses. All three drugs are used as adjunct therapy with LDOPA Ropinirole and Premipexole are used as oral tablets, poor bioavailability because of metabolism Rotigotine is used only as intradermal patches to escape the first pass and phase II metabolism that may occur if the drug if given orally. Notice in Rotigotine, the incorporation of the thiophene ring system (5-membered ring with Sulfur atom) with its sulfur atom increasing lipophilicity to easily cross into the brain.
Pramipexole (Mirapex®)
Synthetic Direct Dopaminergic Agonists
All three drugs are acting as direct dopaminergic agonists at D-2 receptors (they are not prodrugs). All three drugs have common structural features close to the phenyl-ethylamine backbone. All three drugs are used in mg and sub-mg doses. All three drugs are used as adjunct therapy with LDOPA Ropinirole and Premipexole are used as oral tablets, poor bioavailability because of metabolism Rotigotine is used only as intradermal patches to escape the first pass and phase II metabolism that may occur if the drug if given orally. Notice in Rotigotine, the incorporation of the thiophene ring system (5-membered ring with Sulfur atom) with its sulfur atom increasing lipophilicity to easily cross into the brain.
Rotigotine
Synthetic Direct Dopaminergic Agonists
All three drugs are acting as direct dopaminergic agonists at D-2 receptors (they are not prodrugs). All three drugs have common structural features close to the phenyl-ethylamine backbone. All three drugs are used in mg and sub-mg doses. All three drugs are used as adjunct therapy with LDOPA Ropinirole and Premipexole are used as oral tablets, poor bioavailability because of metabolism Rotigotine is used only as intradermal patches to escape the first pass and phase II metabolism that may occur if the drug if given orally. Notice in Rotigotine, the incorporation of the thiophene ring system (5-membered ring with Sulfur atom) with its sulfur atom increasing lipophilicity to easily cross into the brain.
Selegiline (Eldepryl®, EMSAM®)
MAO-Inhibitors
MAO enzyme requires very strict structural requirement in the substrate to be metabolized. The substrate must be primary aliphatic amine, with no substitution on the adjacent carbon (should be CH2). In addition to the above requirements; the primary amine should be separated by a spacer of 2-3 carbons from an aromatic area like phenyl group or indole group. The enzyme has two subtypes: MAO-A, and MAO-B MAO-A metabolizes molecules with either of the two lipophilic areas (nonselective; metabolizes NE, DA, 5HT). MAO-B is elective only for molecules with the lipophilic area as phenyl (as the case is with NE&DA). *MAO-B inhibitors have a very peculiar structural feature that tricks the enzyme: a propyl group with triple bond.The two drugs are selective inhibitors for MAO-type B and are useful as adjunct therapy in the treatment of Parkinson’s disease
Pargyline
MAO-Inhibitors
MAO enzyme requires very strict structural requirement in the substrate to be metabolized. The substrate must be primary aliphatic amine, with no substitution on the adjacent carbon (should be CH2). In addition to the above requirements; the primary amine should be separated by a spacer of 2-3 carbons from an aromatic area like phenyl group or indole group. The enzyme has two subtypes: MAO-A, and MAO-B MAO-A metabolizes molecules with either of the two lipophilic areas (nonselective; metabolizes NE, DA, 5HT). MAO-B is elective only for molecules with the lipophilic area as phenyl (as the case is with NE&DA). *MAO-B inhibitors have a very peculiar structural feature that tricks the enzyme: a propyl group with triple bond.The two drugs are selective inhibitors for MAO-type B and are useful as adjunct therapy in the treatment of Parkinson’s disease
Tolcapone (Tasmar®)
COMT inhibitors (Catechol-O-Methyl-Transferase)
The key structural features of both drugs is the catechol structure and the presence of a nitro group next to the catechol group. Both drugs have very low bioavailability due to first pass metabolism in the liver. The two drugs have difference in the locale of action: Tolcapone, mostly central, Entacapone mostly peripheral. Tolcapone is metabolized by oxidation of the toluene methyl group into carboxylic acid and it inhibits both DA and LDOPA metabolism in the brain. Entacapone is metabolized in by isomerization around the double bond into the inactive “Z” enantiomer. Entacapone inhibits the O-demthylation of administered LDOPA in the periphery increasing its chances to cross into the CNS. * Both drugs are used as adjunct therapy in combination with LDOPA
Entacapone (Comtan®)
COMT inhibitors (Catechol-O-Methyl-Transferase)
The key structural features of both drugs is the catechol structure and the presence of a nitro group next to the catechol group. Both drugs have very low bioavailability due to first pass metabolism in the liver. The two drugs have difference in the locale of action: Tolcapone, mostly central, Entacapone mostly peripheral. Tolcapone is metabolized by oxidation of the toluene methyl group into carboxylic acid and it inhibits both DA and LDOPA metabolism in the brain. Entacapone is metabolized in by isomerization around the double bond into the inactive “Z” enantiomer. Entacapone inhibits the O-demthylation of administered LDOPA in the periphery increasing its chances to cross into the CNS. * Both drugs are used as adjunct therapy in combination with LDOPA
Anticholinergics (lower Ach, raise DA)
Benztropine (Cogentin®)
Atropine
The EPS is normally controlled by a balance between acetylcholine and dopamine. In Parkinson’s, the balance is shifted towards high acetylcholine, low DA as shown below.
Notice tha advantage of Benzotropine over the atropine (the father of all anticholinergics) with that regard: no ester function (ether instead) and more lipophilic character to penterate into the CNS faster
Tryptophan
Precursor of 5HT biosynthesis in the brain
indole ring system
5-Hydroxytryptamine 5HT seratonin
Produced from Trp by the action of 2 enzymes 1. L Amino Acid Aromatic Decarboxylase 2. Aromatic Hydroxylase Actions: controls sleep, mental well-being metabolized by MAO type A, why?
indole ring system
Imipramine
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
tertiary amine, more towards 5HT than NE reuptake blockade: +++5HT/++NE High side effects Long duration of action due to Metabolism by N-demethylation active metabolite (desipramine)
it is still active as itself (not a prodrug)
longer half life
Desipramine
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
secondary amine +++NE/++5HT
shorter half-life
Trimipramine
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
3 methyl groups tertiary amine
+++5HT/++NE
Clomipramine
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
more lipophilicity: better CNS penetration tertiary amine
+++5HT/++NE
Amitriptyline
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
dibenzocycloheptine nucleus
tertiary amine
+++5HT/++NE
Nortriptyline
tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
dibenzocycloheptine nucleus
secondary amine +++NE/++5HT
Protriptyline
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
dibenzocycloheptine nucleus
secondary amine +++NE/++5HT
Saturated double bond of nortriptyline (notice pro from propyl)
Doxepin
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
Dibenzoxapine nucleus, oxygen bioisostere
tertiary amine
+++5HT/++NE
Amoxapine
Tricyclic Antidepressants (TCAs) or “typical” antidepressants)
Antidepressant and antipsychotic (mild) structure unique because the ring portion joining the two benzo's with one atom is non-carbon reversed bridge lowers 5HT affinity and give it some affinity to post synaptic DA (act as antagonist)
Maprotiline
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synapse
More selective toward NE reuptake blockade (high NE/5HT ratio) Weak activity, but low side effects metabolites are inactive mostly aromatic hydroxylation
Trazodone
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Name comes from Triazole/Ketone Piperazine derivative, means CNS or cardiovascular activity only tertiary amine of atypical drugs the rest are 2o . only acts on 5HT reuptake, but low activity low side effects metabolized by aromatic hydroxylation (CYP450)
savere heart effecst making it not a true SSRI
Bupropion
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
affinity at reuptake receptors mostly NE weak antidepressant activity low side effects
Venlafaxine
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Although it is chiral molecule, but it is selective to both 5HT and NE reuptake only, however; the chiral center prevents anticholinergic activity Blocks both NE and 5HT reuptake. +++/+++ Weak antidepressant, but less adverse effects
E demethylation
O demethylation
Phase 2
Nefazodone SSRI
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Differs from Trazodone in having the triazole ring as separate (not fused) This gave selectivity to the 5HT reuptake with almost no side effects. Given twice a day because of first pass aromatic hydroxylation.
low bioavalibity
Fluoxetine SSRI
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Pure 5HT activity Chiral molecule, so does not bind non-selectively to other receptors unlike TCA structure that allows flexible conformations one of the longest half-lives known (7-9 days) (in terms of plasma levels, not action) active enantiomer = R
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Paroxetine SSRI
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
Pure 5HT activity Chiral molecule, so does not bind non-selectively to other receptors unlike TCA structure that allows flexible conformations
Sertraline SSRI
Atypical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
secondary amine nucleus derived from tetra-hydro-napthalene 2 chiral centers
Citalopram and Escitalopram
typical Antidepressants
increase 5HT and NE activities at their receptors by blocking its reabsorption back into the pre-synaps
R is inactive enantiomer Racemic mixture (R&S) (Celexa) Dose 20, 40 mg S is the Active enantiomer (Lexapro): dose 5.10.20 mg
Phenelzine
MAOIs
As for the inhibitors: nonselective MAOIs means it blocks both enzyme subtypes MAO-A and MAO-B. examples: phenylzine, isocarboxazide, tranylcypromine
Hydrazine structure instead of amine
Isocarboxazide
MAOIs
As for the inhibitors: nonselective MAOIs means it blocks both enzyme subtypes MAO-A and MAO-B. examples: phenylzine, isocarboxazide, tranylcypromin
Same like phenelzine but the hydarazin nitrogen Is forming-amid-like bond with isooxazole ring’ more lipophilic and less polar than the hydrazine.
Tranylcypromine
MAOIs
As for the inhibitors: nonselective MAOIs means it blocks both enzyme subtypes MAO-A and MAO-B. examples: phenylzine, isocarboxazide, tranylcypromin
The trick is in the spacer.
Chlorpromazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
weak potency and high side effects
Triflupromazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
strong potency and high side effects
Thioridazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
weak potency, low EPS, high other side effects
low affinity for D2 receptors
Mesoridazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
intermediate potency, low EPS, high other side effects
low affinity for D2 receptors
Prochlorperazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
weak potency, high EPS, low other side effects
Trifluperazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
strong potency, high EPS, low other side effects
Fluphenazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
strong potency, high EPS, low other side effects
oral or made into Depo for injection
Perphenazine
Phenothiazine antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
weak potency, high EPS, low other side effects
oral or made into Depo for injection
Chlorprothixene
Phenothiazine-like nuclei (thiothixenes)
antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
Not very potent, side effects high
Thiothexine
Phenothiazine-like nuclei (thiothixenes)
antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
very potent, high EPS, low other side effects
Flupenthixol
Phenothiazine-like nuclei (thiothixenes)
antipsychotic D2 antagonist
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
very potent, high EPS, low other side effects
Made as HCl salt or ester for IM injection (depo)
Haloperidol
Butyrophenones
atypical antipsychotics
High EPS, less of other side effects More dopamine receptor specificity
Used to treat schizophrenia, Gill de la Tourette Syndrome, Bipolar Depression
may increase suicidality, very good for Tourette's and schizophrenia
used orally as-is, can be made as decanoate ester for IM injection
smaller lipophilic area creates less affinity for side-effect targets
drives to D2 better
Droperidol
Butyrophenones
atypical antipsychotics
High EPS, less of other side effects More dopamine receptor specificity
Used to treat schizophrenia, Gill de la Tourette Syndrome, Bipolar Depression
No OH group = no IM formulation
Pimozide
Butyrophenones
atypical antipsychotics
High EPS, less of other side effects More dopamine receptor specificity
Used to treat schizophrenia, Gill de la Tourette Syndrome, Bipolar Depression
Very potent
dosed at 0.1-0.3mg
Risperidone
Butyrophenones
atypical antipsychotics
High EPS, less of other side effects More dopamine receptor specificity
Used to treat schizophrenia, Gill de la Tourette Syndrome, Bipolar Depression
Ziprasidone
Butyrophenones
atypical antipsychotics
High EPS, less of other side effects More dopamine receptor specificity
Used to treat schizophrenia, Gill de la Tourette Syndrome, Bipolar Depression
Loxapine
Antidepressants TCAs with antipsychotic secondary effect
low side effects
weak antipsychotic, but good for dual effects
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
Clozapine
Antidepressants TCAs with antipsychotic secondary effect
low side effects
weak antipsychotic, but good for dual effects
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
Olanzapine
Antidepressants TCAs with antipsychotic secondary effect
low side effects
weak antipsychotic, but good for dual effects
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
Quitiapine and clotiapine
Antidepressants TCAs with antipsychotic secondary effect
low side effects
weak antipsychotic, but good for dual effects
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
Molindone
Morpholine and Indole-derived nuclei
Antidepressants TCAs with antipsychotic secondary effect
low side effects
weak antipsychotic, but good for dual effects
Side effects Anticholinergic (acetylcholine) Sedation (5HT) Hypotension (NE) Antihistamine (H1-peripheral receptors and on MAB) Extrapyramidal symptoms (EPS), causing eps is due to blocking dopamine receptors
