PD MedChem

Dopamine Receptors

In the basal ganglia circuitry, there are 2 pathways from the cortex: direct & indirect.Direct enables movement Indirect inhibits movement

Excitatory: D1 type (D1 & D5)

Coupled to Ga2, activating the cyclic AMP-PKA pathway

Subtopic

Inhibitory D2 (D2, D3, & D4)

Coupled to Gi/o, decrease cAMP, inc K current and dec voltage gated Ca currents

Processes under Dopaminergic control:
-reward
-emotion
-cognition
-memory
-motor activity

-DA is a modulator of neurotransmission (not excitatory or inhibitory)
-Loss of DA in the striatum --> reduced excitatory input to the cortex

Low DA conc. --> D1 R stim --> vasodilation + ortho hypoTN

Mod DA conc. --> B adrenergic R --> inc cardiac contractility

High DA conc --> a adrenergic R --> vasoconstriction + life threatening HTN

Metabolism of DA & L-Dopa

Metabolism of DA:
-COMT
-MAO

In the metabolism process, only 1% of orally admin L-Dopa reaches the brain as DA
--> Solution: halting the conversion of L-Dopa to DA in the periphery should boost L-dopa taken up into CNS

Carbidopa/Levodopa

-+ of carbidopa can extend the elimination half-life of L-dopa
-cabidopa is NOT CNS penetrant (unlike L-dopa), and is inhibitor of AADC

ADEs:
-N/emesis --> greatly reduced by reduction in peripheral DA concentrations
-chronic use of L-dopa --> prominent dyskinesias

Enhancing DA exposure in CNS:

Halting the peripheral metabolism of L-dopa shunts metabolic pathway to COMT --> inhibition of peripheral COMT --> extension of half-life of L-dopa --> more L-dopa uptake into the CNS

PD Agents

reversible COMT Inhibitors

Tolcapone

-Longer DOA
-reduce wearing off symptoms of pts on L-dopa
-acts both in the CNS and periphery
-black box warning due to 3 fatal cases of acute liver failure

Entacapone

-shorter DOA
-only acts in periphery
-reduce wearing off symptoms of pts on L-dopa
-available in fixed dose combo w/ carb/levo

MOA:

L-dopa metabolism inhibited in periphery --> Inhibit DA metabolism by COMT in the CNS --> enhance L-dopa DOA

Monoamine Oxidase Inhibits (MAOis)

MAO-A/B both capable of oxidizing DA Long-acting, Irreversible, non-selective inhibitors of MAO-A/B are CI w/ L-dopa due to the risk of inducing hypertensive crises (cheese effect)SELECTIVE inhibitors are required***Ex of non-selective: phenelzine or tranylcypromine

Selegiline

-Selective** irreversible inhibitor of MAO-B
-SAR: terminal alkyne is the functional group that forms the covalent bond w/ protein

CYP-mediated N-dealkylation produces amphetamine metabolites --> POTENT vasoconstrictors

Rasagiline

-Class/MOA same as above
-DOES NOT produce amphetamine metabolites

Safinamide

-Modulate dopaminergic & glutamanergic signaling via multiple mechanisms:
-MAO-B inhibition (reversible, 1000x selective for MAO-B)
-modulation of certain Na/K channels
-use: reduce "off" time and extend "on" time without dyskinesias in pts taking carb/levo
-no effect on BP/HR
-CI w/ certain antidepressants due to risk of serotonin syndrome
-Metabolism: non-p450 mediated

Dopamine Receptor Agonists

neurodegeneration occurs w/ progressive PD --> fewer striatal nerve terminals available to decarboxylate L-dopa Solution: drugs that are CNS penetrant + directly stimulate DA receptors DA RA: longer DOA vs. L-dopa --> less likely to induce on/off effects/dyskinesias Other ADEs are inc relative to L-dopa, incl N/V, sedation, vivid dreaming and hallucination RA = receptor agonist

Ergot Alkaloid

Non-selective (5HT + adrenergic R activity) carry risk for serious cardiac complications newer non-ergot DA RA are generally safer alts

Bromocriptine

-partial agonist at D2/3
-1st direct DA RA used in the txt of PD

Cabergoline

-full D2 agonist + partial agonist at D3/4 w/ long half-life (48hrs)

Non-ergot DA Receptor agonists

Pramipexole

-agonists of all D2 Rs and among the most commonly prescribed direct DA RA for PD

Ropinirole

-agonists of all D2 Rs and among the most commonly prescribed direct DA RA for PD
-metabolized by CYP1A2

Rotigotine

-New D1/2/3 agonist delivered as transdermal path to provide 24hr coverage
-NOT affected by hepatic/renal/CYP-mediated so DDI are not sig

Muscarinic Acetylcholine Receptors

Family of CGRPs that respond to the binding of AChDopamine and ACh have a reciprocal rs in the nigrostriatal dopamine pathway Normally dopamine suppresses cholinergic activity Removal of dopamine --> inc in ACh activity --> extrapyramidal symptoms (EPS) --> tremors experienced by PD pts Antagonists of muscarinic ACh receptors offer potential therapeutic benefitSAR: Similar to antihistamine disphenhydramineMost serious ADEs: sedation + mental confusion

Trihexphenidyl, benztropine

N-methyl-D-aspartate receptor

Overactive glutamate transmission = L-dopa induced dyskinesias (LIDs)Excessive glutamate --> excitotoxicity NMDA is an ion channel found in nerve cellsAmantadine an NMDA antagonists --> txt of LIDs in PD pts NMDA antagonists (PCP, ketamine) --> psychotomimetic effects

Amantadine

-NMDA antagonists
-treats L-dopa induced dyskinesias (LIDs) in PD pts
-similar in SAR to Alzheimer's drug memantine
-basic amine, protonated at physiologic pH
-lipophilic cage --> CNS entry
-ADEs: confusion, hallucinations

Treatment of Symptoms

inc DA --> hallucinations and delusions muscarinic/NMDA antagonists --> similar ADEs 1st: adjust meds w/o worsening PD motor symptoms

Hallucinations/Delusions

Atypical antipsychotics (2nd gen):
clozapine or quetiapine

Pimavanserin: agonist of 5-HT, FDA for
hallucinations/delusions in PD pts

"Off" episodes

Istradefylline

-functionalized derivative of caffeine
-antagonist of adenosine A2a receptors
-potentiate the antiparkinsonian action of L-dopa
-useful in reducing "off" eps b/w doses
-dose adjust req w/ strong CYP3A4 inhibitors + impaired hepatic function
-CI w/ CYP3A4 inducers
-cause/exacerbate LIDs + psychosis