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Lecture 1 Intro To CNS Drugs

The document discusses several classes of central nervous system drugs including NMDA receptor antagonists, GABA receptor agonists, serotonin receptors, dopamine, endocannabinoids, and orexin/hypocretin. NMDA antagonists are used for conditions like ischemia and motor disorders. GABA agonists include benzodiazepines, barbiturates, and neuroactive steroids. Serotonin receptors are involved in appetite, anxiety, migraines, and schizophrenia. Endocannabinoids and orexin/hypocretin regulate processes like sleep, metabolism, and reward.

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39 views

Lecture 1 Intro To CNS Drugs

The document discusses several classes of central nervous system drugs including NMDA receptor antagonists, GABA receptor agonists, serotonin receptors, dopamine, endocannabinoids, and orexin/hypocretin. NMDA antagonists are used for conditions like ischemia and motor disorders. GABA agonists include benzodiazepines, barbiturates, and neuroactive steroids. Serotonin receptors are involved in appetite, anxiety, migraines, and schizophrenia. Endocannabinoids and orexin/hypocretin regulate processes like sleep, metabolism, and reward.

Uploaded by

drunkenwukong
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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L1: Intro to CNS Drugs

NMDA receptor antagonists Ischemia:


- inotropic glutamate - excitotoxic damage occurs in people who experience brain ischemia  due to stroke or MI
receptor = excitatory - ischemia  massive glutamate release in area  prolonged NMDA receptor activation
- high levels of - antagonists MAY be helpful  to reduce ischemic cells loss, but adverse SE
glutamate toxic to - Glycine site antaonists may be more promising
neurons!
- Domoic acid  Motor movement disorders:
produced by marine
algae, CNS effects ALS  abnormalities in EEAT2 in afected areas of CNS
include headache, - Riluzole  blocks glutamatergic neurotransmission (NMDA antagonist)
dizziness, mental
confusion, muscle Parkinson’s disease:
weakness, and possible - amantadine  weak noncompetitive, low affinity antagonist of NMDA
short term memory - has dopamine releasing properties
loss - also for adjunctive therapy in tx of catatonic syndromes

Learning and memory:


- NMDA receptor activation necessary for induction of hippocampal memory formation LTP; Ca
- LTP: process of synaptic strengthening  learning/memory
- Memantine  noncompetitive, low affinity NMDA antagonist for Alzherimer’s disease  reduces
excitotoxicity

Anesthesia:
- Ketamine  NDMA receptor noncompetitive antagonist
- A dissociative anesthetic: peds and vets
- Also abused as recreational drug (PCP too)

GABA A receptor agonists Muscimol


- A: inotropic - classic agonist
- B: metabotropic - found in mushroom: amanita muscaria
- Inhibitory - sedative-hypnotic and psychoactive hallucinogen
- hyperthermia, mydriasis, mood elevation, anorexia, ataxia, hallucinations
Barbiturates:
- bind to barb. Site of GABA A receptor complex and faciliate actions of GABA
- can activate GABA a receptor directly at high doses  increased duraiton of ion channel openings

Benzodiazepines:
- bind to benzo site on GABA A receptor (alpha 1, gamma 2) & facilitate action of GABA
- do NOT activate it directly  allosteric modulation  increase frequency of ion channel opening
GABA A receptor agonists
Cont’d Ethanol
- enhances GABA a receptor activity in addition to other NTs/receptors
- mechanism not entirely clear

Neuroactive steroids:
- made in brain
- act as lcoal signaling mechanisms rather than hormones
- ex: allopregnanolone, pregnenolone, DHEA
- can enhance or inhibit GABA
- involved in: mood, learning/memory, stress, seizures, sleep

Convulsants
- both competitive and noncomp. Antagonists
- NO therapeutic use
- Example: bicuculline, picrotoxin, pentlenetetrazol

Antiseizure/epilepsy:
- Tigabine
- Selective inhibitors of GAT -1  elevates extracellular GABA and potentiates transmission
- Protects against seizures
- Vigabatrin
- Irreversible inhibitor of GABA – T  prevent GABS metabolism
- Indicated for infantile spasms (monotherapy) and as adjunctive for adults with refractory complex partial
seizures with no response to other drugs
GABA B receptor agonists Baclofen:
Coupled to Ca++ or K+ via - agonist
second messenger systems - centrally acting muscle relaxant/antispasmodic
- tx for alcoholism?

GHB:
- sodium oxybate
- weak agonist, made from GABA
Activation of receptor  ↓ in - indicated for narcolepsy
Ca++ conductance, activates K+ - a date rape drug
channels (hyperpolarization
 neuronal inhibition)

Serotonin 5-HT1A receptors


- agonists here will:
- induce hyperphagia  stimulation of autoreceptors  inhibits activity of 5-HT ergic neurons  decrease
in 5-HT release in forebrain  reduced appetitie and food intake
- reduce anxiet  Buspirone
- reduce alcohol intake in rats
- induce hypothermia

5-HT 1B/1D receptors


- agonists: tx of migraine headaches
- activation of receptors  cranial VC, inhibited release of proinflammatory neuropeptides  reduced
transmission in pain pathway (trigeminal)
- Triptans: sumatriptan, frovatiptan, naratiptan, rizatriptan, almotriptan, zolmitriptan, eletriptan

5-HT 2A receptors:
- located in cerebral cortex, striatum, nucleus accumbens, etc
- agonists are hallucinogenic (LSD?)
- antagonists at these receptors  treatment of Schizophrenia  Ritanserin, clozapine, risperidone

5-HT 3 receptors:
- antagonists used to prevent or reduce nausea/vomiting due to surgery, chemo, etc
- example: granisetron, odansetron, dolsaetron, palonsetron
Dopamine: Involved in reward, addiction, and movement/motor

Endocannabinoids GPCRs
2 primary endogenous cannabinoids:
- anandamide & 2arachidonylglyercol
- made from arachidonic acid
- involved in memory, cognition, immunomodulation, appetite, and pain perception

Orexin/hypocretin Produced in lateral/posterior hypothalamus


Also release glutamate  excitotoxic

Involved in sleep/wake cycle, metabolism, food intake, mood, reward


Narcolepsy with cataplexy often due to lack of it

Suvorexant:
- antagonist at OX1 and 2 for inomnia

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