Exam 2 Lecture 20, Med Chem Anti-PD drugs

Benzene Ring with 2 OH Amine with 2 carbon Linker

L-Tyrosine

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)

Attacks the NH2 and turns into COOH

Attacks OH and turns to CH2O

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+

Nigrostriatal Cell death via inhibition of NADH Oxidation Depletes nigrostriatal neuronal cells of ATP Taken up via catecholamine neruons

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

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

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

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

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

crosses BBB via amino acid transporter easily decarboxylated by L-AAAD into dopamine

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

Forms a covalent bond with DOPA decarboxylase, “killing the cofactor”

Dopamine agonist with longer duration (8-24h) compared to levodopa (6-8h)

Benzene ring with 2 carbon linker to NH as skeleton of molecule

Long acting

Short acting, last resort

trans, a/b - rotamer are potent cis, a - rotamer is not potent

liver, GI, placenta

CNS glial cells and in blood platelets

selective inhibitor of MAO-B alone not super useful, used with levodopa metabolized into I-amphetamine, DNRI = contribute to stimulatory effects on locomotor activity Suicide substrate - binds irreversibly

prolong effect of carbidopa-levodopa therapy by blocking COMT that break down DA Side effects: nausea vivid dreams, confusion and hallucinations