Exam 2 Lecture 20, Med Chem Anti-PD drugs Flashcards
Identifying Catecholamine
Benzene Ring with 2 OH
Amine with 2 carbon Linker
Rate Limiting In L-DOPA biosynthesis
L-Tyrosine
Current pharmacotherapy is symptomatic via following means
Stimulation of DA release from presynaptic sites
Augmentation of synthesis of brain DA
Direct stimulation of DA receptors
Decreasing reuptake of DA at presynaptic sites
Decreasing dopamine catabolism (MAO-B and COMT inhibitor)
MAO acts on…
Attacks the NH2 and turns into COOH
COMT acts on…
Attacks OH and turns to CH2O
MPTP to MPDP+ transformation
Occurs in MAO-B rich glial cells near striata nerve terminals
NOT mediated in target nigrostriatal neurons because MAO-B is not present there
MPDP+ diffuses out of glial cells and oxidized to MPP+
MPP+ causes…
Nigrostriatal Cell death via inhibition of NADH Oxidation
Depletes nigrostriatal neuronal cells of ATP
Taken up via catecholamine neruons
AntiCholinergic therapy
Symptomatic relief through restoration of balance between neurotransmission by ACh and DA in basal ganglia
Found that drugs which increase cholinergic neurotransmission aggravate Parkinsonism in humans
Antagonists of muscarinic acetylcholine receptors (mAChRs) in the CNS tend to diminish the characteristic tremor of Parkinsonism
Anticholinergic drugs rarely produce more than 20% improvement
SAR of ACh Receptor ligand
Replace acetate moiety with bulky, lipophilic structure leads to anticholinergic action
conversion of polar 4 ammonium to 3 amine allows for drug to get into CNS due to greater lipid solubility of 3 amine.
3 amines less potent receptor antagonists but have greater selectivity for mAChRs vs nAChRs, and have antagonist property for other receptors like H1 and D2
How to tell if anticholinergic agent will cross BBB
4 amine will not cross BBB, you want to look for ones that are 3 amines since they will cross. All examples given were 3 amines
Amantadine
Approved 1966, found to be useful in reducing PD symptoms accidentally 1969
releases DA from intraneuronal storage sites as well as delays re-uptake of DA by nerve terminals and has significant antiparkinsonian effects which are enhanced with levodopa. Can be used as single or combo therapy
pKa 9, at body pH its ionized but it can cross BBB due to its cage-like structure.
Cage-like structure increases its lipophilictiy and prevents catabolism, its excreted in urine unchanged
Why cant use just dopamine
Dopamine cannot access the CNS from periphery due to….
Structural hydrophilicity and less lipophilicity
Ionization, mostly protonated at body pH
Peripheral metabolism reducing bioavailability to CNs
L-DOPA is effective because
crosses BBB via amino acid transporter
easily decarboxylated by L-AAAD into dopamine
Problems with L-DOPA admin
Issue:
Due to activity of L-AAAD, you get a lot of dopamine in the periphery which activates a and b adrenergic receptors causing vasoconstriction and enhancing heart rate
solution:
Admin with carbidopa, L-AAAD inhibitor prevents metabolism in periphery and it cant cross BBB so doesn’t affect metabolism in CNS
Carbidopa mechanism
Forms a covalent bond with DOPA decarboxylase, “killing the cofactor”
