Professional Documents
Culture Documents
Neuropharm Ex 4
Neuropharm Ex 4
Phosphatase Inhibitors
Okadaic acid inhibits PP1 and PP-2A
Deltamethrin inhibits calcineurin
Cyclosporin inhibits calcineurin
←
←
←
←
04/05/2009 19:59:00
← Ion Channels: Depolarizing
← Ionophores: non-gated channels
← Toxins
• Monensin
o Source – Bacteria
o Mechanism of Action
Macro – antibiotic
Micro – Na+ ionophore
• Amphotericin
o Source Strepococcus
o Mechanism of Action
Macro – antifungal and antiprotozoal
Micro – NA+/K+ ionophore
←
← ATPases (pumps) can change membrane polarization
• Na+/K+-ATPase
o For every 3 Na+ pumped out, 2 K+ ions enter the cell;
causing a hyperpolarization.
←
← Pump toxins disrupt function
← Toxins
• Digitalis
o Blocks NA+/K+ ATPase by inhibiting dephosphorylation
• Ouabain (wabain)
o Blocks NA+/K+ ATPase
• Thrapsigargin
o Blocks Ca2+ATPase in ER
Depolarizing channels
• Voltage-gated
o Na+ channels
o Ca+2 channels
←
← Gating Models
• *Regional conformational change – a selective portion of the
protein structure changes
• General conformational change – entire structure changes
• *Blocking particle
← * most likely to be the cause
←
← Three kinetic steps
• Open inactivation closed
• The inactivation gate (msec) will be much slower than the
activation gate (nsec)
←
← Voltage-clamp single-channel recording
• The voltage would rise during the Voltage command step
• The current opens during the command step and it shuts off but the
voltage still remains depolarized.
←
← Active, inactive and closed
• In the inactive state there is no current but the voltage still remains
depolarized.
←
← Cahnnel structure conservation
← Na and K channels end up being made up of a single protein. There is
an open central space. There are inactive regions and active regions within
the protein.
←
← Visualizing Na channels
← 4 subunits with 6 transmembrane segments each
← Na channel types NaV1.x don’t need to know
←
← Local anesthetics block Na+ channels
• Cocaine
• Lidocaine widely used because of less cardiac and liver toxicity
←
← TTX block Na+ channel conductance
• Fugu fish (sushi)
←
← Additional Na+ channel blockers
← Toxin
• Saxitoxin (STX) red tide
• Tetrodotoxin (TTX)
• QX-314 works from the inside, used in recording electrode to
selectively turn off neurons individually
←
← Cardiostimulants prevent inactivation of Na+ currents
• Aconitine – monks hood
• Veratridine – rhizomes of sabadilla lily
← * both are considered neurotoxins but may be used for very low heart
rates
←
← Intracellular Ca2+ channels
• IP3 (neurons and muscles)
o IP3 is the agonsist
o Heparin (blood thinning agent) and caffeine are antagonists
• Ryanodine (skeletal muscle, cardiac muscle, neuronal)
o Ryanodine, caffeine, and heparin are all agonists
o Dantrolene is the antagonists
←
← Ca2+ channel subunit structure
← 4 subunits with 6 transmembrane domains each
←
← Two major types of Ca2+ channels
• LVA (low-voltage activated)
o Rapidly inactivating
• HVA (high-voltage activated)
o Inactivating
o Noninactivating
←
← 2/12/09
← Voltage-dependent Ca2+ channel (VDCC) types
← L
• Found in neuronal (CaV1.2-1.4) and muscle (CaV1.1) cells
• HVA & noninactivating
• Blocked by inorganic ions (cobalt, cadmium)
← T (transient)
• Cardiac, Nuronal (CaV3.1-3.3)
• LVA and Fast Inactivating
← N
• Neuronal only (CaV2.2)
• HVA and Slow Inactivating
← P/Q (purkinje) and originally thought to be presynaptic but also in
postsynaptic
• Neuronal only (CaV2.1)
• HVA and Slow Inactivating (but not as slow as N type)
← R (found originally in retina)
• Neuronal Only (CaV2.3)
• HVA and Fast Inactivating
←
← Organic Ca2+ channel toxin sources
• Spiders, snakes, tree roots, and microorganisms
←
← Ca2+ channel Ligands I
← Blocks L types
• Dihydropyridine
o Nifedipine – widely used for hypertension to regulate heart
rate and cardiac output
o Nimodipine – Brain specific
• Arylalkylamine
o Verapomil
• Benzothiazepine
o Diltiazem
• Alkaloids
o Phloretin (plumb tree roots)
← Blocks T type
• Benzimidazole
o Flunarazine
o Mibefradil
← Blocks N type
• Conotoxin peptides
o Ω-CTX-GVIA (conotoxin gene 6 A)
← Blocks N, P/Q
• Conotoxin peptides
o Ω-CTX-MVIIC
←
← Ca2+ channel ligands II
← Enhances L type
• BAY-K-8644
← Enhances ALL types
• Maitotoxin
← Blocks P/Q (funnel spider toxin)
• Omega-Aga-Ia
← Blocks L type
• Phloretin (fruit tree root alkaloid
Blocks ALL types
• Inorganic ions (Mg2+, Cd2+, Cs2+, Ni2+, Co2+)
← ** barium flows through Ca2+ channels better than Ca2+
←
← Ca2+ homeostasis in neurons
← Ca2+ Influx
• VDCCs
• NRs (NMDA receptors)
• Na+/Ca2+ exhanger
← Ca2+ stores
• CaBPs
• ER
• Mitochondria
← Ca2+ release
• IP3Rs
• RyRs
• Ca2+ dependent
• Ca2+ release
← Ca2+ Efflux
• ATP-ases
• NA+/Ca2+ exchanger
←
← Ca2+ imaging with fluorescent indicators
• Fura 2 most commonly used
←
← Voltage-Gated Channels: Hyperpolarizing
• Chloride (Cl-) channels
• Potassium (K+) channels (K channels can flow inward if the cell is
above than the resting potential or outward if the cell is below the
resting potential voltage -65mV.
←
← Chloride Channel Toxins
• Chlorotoxin
• Flufenamate (chlorea use)
• Tamoxifen (breast cancer treatment)
←
← K+ Channel toxin sources – organic and synthetic
←
← 4 major classes of K+ channels
• Voltage-Dependent K+ channels (VDKC)
o Ia (first observed),
o Id (delayed),
o Ik,
o Im (muscurine sensitive)
• Rectifier (making right returning to right potential) K+ channels
o Ik,
o anomalous rectifier (activated by below resting potential),
o Ih(queer) – hyperpolarization activated
o tandem pore – form two channels per molecule
• Metabotropic-Gated K+ channels
o Im (metabotropic regulated)
o ATPsensitive (requires ATP)
o Iahp (After hyperpolarization potential)
• Ca2+-dependent K+ channels (CDKC)
o Ic (calcium)
o Im
o Iahp
←
← 2/17/09
← VDKC structure (Ia, Id, Ik)
• 4 separate subunits with 6 transmembrane segments each
←
←
← K+ currents and action potential firing
← Ia and Id are the first to be activated and try to keep the action
potential back to resting. As the voltate rises up then the delayed rectifier
Ik and brings the resting potential. Then Ca dependant K channels are
activated . Then the Ic, Im, Iahp to lower the after hyperoplarization
potential. Then the slowIAHP, and ISahp. These determine ability for a
neuon to fire again. If we reduce the capacity for the Ic, Im, Iahp, I ahp, &
Isahp.
←
← VDKCs (see notes)
← Ia
• LVA and Fast inactiating
• Blockers – DTX (dendrotoxin)
Id
• LVA
Ik
• Activation – HVA
• Inactivating – SI
• Blockers – Cs+
Tandem pore
• Activation – voltage independant
• Inactivating – SI
• Activators
o Halothane
o Isoflurane
• Blockers – none known
← Anomolous rectifier (inward rectiviers)
• Activation – HA (hyperpolarization activated)
• Inactivating – SI
• Blockers – CS+
← Ih
• Activation – HA (hyperpolarization activated)
• Inactivating – SI
• Blockers – Cs+
←
← Metabotropic-Gated channels
← Im
• Channel proteins KCNA1-5
• Ca2+ sensitivity- High
• Neurotransmitter sensitivity – Muscarinic Ach agonist
• Activation - LVA
• Inactivation - NI
• Activators - retigabine
• Blockers – linopirdine, muscarinic agonist
← Iatp
• Channel proteins – Kir6.x
• Ca2+ sensitivity - insensitive
• Neurotransmitter sensitivity - ATP
• Activation - None
• Inactivation - NI
• Activators – ninoxidil (blocks conversion of testosterone to dht)
• Blockers – ATP
← Iahp
• Channel proteins – 2 or more families
• Ca2+ sensitivity – high
• Neurotransmitter sensitivity – NE, DA, 5HT, Glu
• Activation
• Inactivation
• Activators
• Blockers
←
← CAM and SK-channels
• CAM remains constitutively bound to SK channels, acting as their
Ca2+ sensor
• Apamin (bee venom) binding to SK channel
←
← CDKCs
← Im
• Channel proteins
• Ca2+ sensitivity - low
• Neurotransmitter sensitivity - NO
• Activation
• Inactivation - SI
• Activators - retigabine
• Blockers – linopirdine
← Ic
• Channel proteins - BK
• Ca2+ sensitivity - >1uM
• Neurotransmitter sensitivity - Yes
• Activation
• Inactivation - SI
• Activators - Niflumate
• Blockers – charybdotoxin & TEA (uM)
← Iahp
• Channel proteins - SK
• Ca2+ sensitivity – 200-600nM (CAM)
• Neurotransmitter sensitivity - No
• Activation
• Inactivation - NI
• Activators
• Blockers – apamin, dequalinium, neurotransmitters
← IsAHP
• Channel proteins - ???
• Ca2+ sensitivity
• Neurotransmitter sensitivity - no
• Activation
• Inactivation - NI
• Activators
• Blockers – neurotransmitters – via PKA PKC and CAMKII
metabotropic pathways
←
← Comparing CDKCs – The last three are the AHP portion of the neuronal
firing
←
← 2/19/09
← Glutamate receptors
← Ligand gated Rs: non-NMDA-rs
← Ionotropic neurotransmission – cell neighboring another cell that fires
can also have an excitatory post synaptic potentials. Glutamate is the
neurotransmitter that brings about EPSPs (Glu for short). Inhibitory (IPSPs)
are GABA modulated. EPSP depolarize and IPSP hyperpolarize. They are
not separate from each other but sum. The sum of the two identical units of
stimulation from both EPSP and IPSP is still an inhibition not an excitation!
You need a larger amount of excitation than inhibition (they are not linear
function).
←
← Excitatory amino acids
← Glu
← AMPA
← KA
← NMDA
←
← Defining GluRs by regional ligand binding
← AMPA the most abundant receptor type in nervous systems
← Defining GluRs by effector mechanisms
• AMPA is part of the receptors for Sodium (Na+) channels
← Protein Homology (genes also)
← AMPARs
• Glu R1-R4
← KARs
• Glur5- glur7
• KA-1 & KA-2
← Defining GluRs by gene expression
←
← GluRs subunits form tetramers
← AMPARs typically contain at least one GluR2, at least one other
subtype, thus act as Na+ channels (hill coefficient = 2)
←
← GluR biology: unique GluR2 subunits. Amino terminals on exterior and
carboxyl group in the cytosol. There are 4 membrane spaning and a subunit
Q/R site where you can either have a Q = Gln or R = Asp. That area
determines the specificity for Na+ if not then they will also allow Ca2+ ions
through also. The flip-flop site where alternative splicing determines
polyamine sensitivity. The sensitivity will increase the amount of Na+ influx
under the right conditions.
←
← Agonist
• AMPA – best activator of receptors (but exogenous)
• Glu (endogenous)
← Antagonist (all competitive)
• NBQX (blocks AMPA receptors)
• CNZX (block KA receptors
← AMPAkines (inc. affinity of AMPARs for Glu)
• Aniracetam (enhances Glu binding to receptors)
←
← KAR ligands
← Agonist
• KA (best activator or receptors
• Glu
← Antagonist (all competitive)
• CNQX
←
← Receptor desensitization
← Receptor – AMPA ; cyclothiazide removes desensitization
← Receptor – KA ; concavilin A (conA) removes desensitization
epilepsy possibilities
←
← Iontropic effects of Glu
← AMPA receptors and NMDA receptors. An EPSP (voltage) and EPSC
(current (mA)) create an action potential.
←
← Glu EPSPs are typically mediated by multiple receptor types.
←
← Glu: multicomponent EPSCs See notes
←
← Sulfur-containing EAA transmitters
← Homocysteic acid – produced an anoxious state drownding and
taurine does not cross the blood brain barrier but in diseased states then it
stimulates the inhibitory function.
←
← 2/24/09
← Glutamate
← Defining NMDARs by gene expression
← Ionotropic NMDA, AMPA, Kainate (functional classes)
← NMDA gene families (NR1, NR2a-d, NR3a &b)
← Typical NR = 2 NR1 + 2 NR2 subunits
←
← NR subunit expression varies regionally
← NR1 are found everywhere in the brain
← NR2a – d are regionally distributed
← Ex: RN2a are found in hypocampus & Nr2c – cerebellum
←
← Unique protein structure of NRs – NR= 2 NR1, 2 NR2 (dual-
heterodimer = tetramer) The subunits NR2 determine the flow and
glutamate binds to the NR2s. The NR1 have binding sites for glycene (Gly).
The receptors have a co-agonist… it requires all sites activated (2 gly and 2
glu) *unique
←
← Functional analysis of NRs (see notes)
←
← Uses/abuses of NMDAR ligands
• Therapuetic
o Dissociative anesthesia
o Cough suppression
o Learning and /or memory enhancement
o Stroke/drowning/ischemia neuroprotection
• Non-therapuetic
o Dissociative hallucinogen
←
← PCP
• Antagonist – blocks open channel
o PCP (phencyclidine; angel dust)
o MK-801 (dizocilpine)
o Angeldustin (endogenous)
o Ketamine (veterinary practices)
o Dextromethorphan (robitusin)
o Memantine (memory treatment in Alzheimer’s)
← Mg++
• Antagonist – blocks open channel
o Mg++
o Memantine
← EtOH
• Antagonist – blocks channel opening
o EtOH (ethanol)
← Polyamine
• Antagonist – decrease (ANT) Glu binding affinity
o Ifenprodil
o Cadaverine (endogenous)
• Agonist – increase (AGO) Glu binding affinity
o Spermine
← Heavy Metal
• Agonists – prolongs open channel
o Zn++
← HPO4-
• Agonist – prolongs open channel
o HPO4-
←
← “Use-dependent” Mg++ block 1
← When magnesium isn’t present there is a continuous opening but with
normal [Mg++] it will “flicker”
←
← NR noncompetitive antagonist impair learning
← PCP people cannot learn very well
←
← Regulation of NRs by phosphorylation
← NMDAR is attached to PSD-95 connected to other proteins and mGluR
is bound to the homer, which can cause phosphorylation of the NMDA
receptor and enhances the current flow. Review Hammond…
←
← Excitotoxicity via NRs
← NMDA induced apoptosis via Ca++ influx… APV, MK-801, Kyn block
apoptosis
←
← NR2 Glu-binding site ligands
• Agonists
o NMDA (N-methyl-Daspartate)
o Glu (glutamate) (endogenous)
• Antagonist (competitive)
o APV (AP5 = D-amino-phosphovaleric acid) higher affinity
than glutamate but it doesn’t cross the BBB
o CPP (crosses the BBB)
←
← NR2 antagonist impair learning
← - adding APV to mice will greatly impair their learning
←
← NR1 Gly-binding site ligands
• Agonists
o Ser (serine *endogenous via glial cells)
o Gly (glycine *endogenous)
• Partial agonists
o DCS (D-cycloserine)
• Antagonist (competitive)
o Kynurenate (kyn *endogenous)
←
← Gly or Ser as a coagonist of NRs
←
← NR roles in plasticity
← Antagonists block learning, and agonists generate seizures
←
← 2/26/09
← Inhibitory amino acid receptors – GlyRs, GABAARs, GABACRs
←
← 5pm Friday study review.
←
← Pentameric receptors (five sets of subunits make up their structure)
← GABA-A – contain alpha and beta subunits (and gama)
← GABA-C – contains rho subunits
←
← Structural conservation between inhibitory Rs
←
← GlyR anchoring to the cytoskeleton, “clustering”
← They are attached to gepherin to form the clusters and attracted to
microtubules and neurofilaments and other gephrin. If there is a knockout of
the gepherin the GlyRs are not clustered and inhibition is affected.
←
← GlyR activated IPSPs (hyperpolarization of the membrane). Activation
of the receptors cause and influx of Cl- ions.
←
← GlyR activated IPSCs has a hill coefficient of 2
←
← GlyR ligands (strychnine sensitive)
← Agonists (competitive)
• Gly
• Taurine
← Partial agonists (competitive)
• B-aminobutyrate (BABA)
← Antagonists (competitive)
• Strychnine (muscle spasms and breathing issues)
← Antagonists (noncompetitive)
• Picrotoxin
• Picrotoxinin
←
← Regional heterogeneity of GABAAR alpha subunits
Was the 1st receptor purified, sequenced, cloned, imaged via torpedo fish
studies.
nAChR alpha 7 receptors and smoking. An all alpha 7 monomer where all
the 5 subunits are identical.
3/24/09
AChE ligands I: Organophosphates – the ACh is left inside the synapse and
the AChE isn’t able to do its job.
Ligand Duration Use (dose dependant)
Long Irreversible Insecticide WMD
Sarin [GB] X X
DDT X X
Diazinon X X
Malathion X X
AChE Ligands II: Clinical AChE drugs
Inhibitor Duration
Short Long
Donepezil (Aricept) X
Physostigmine X
5 Classes of mAChRs
Name M1 M2 M3 M4 M5
Effectors Gq Gi Gq Gi Gq
Evens Odds
- ↓ AC - ↑ PLC
- Modulate IM
Uses/abuses of mAChR ligands
- Clinical
o reduce secretions (atropine)
o prevent motion sickness (scopolamine)
o treat Alzheimer’s (Donepezil)
o treat autonomic disorders (M3 ANT)
o dilate pupils for ophthalmic exams (M3 ANT)
o treat severe diarrhea (M3 ANT)
o slow heart rate (M2 AGO)
o treat mushroom/anti-AChE poisoning (atropine)
- Non-clinical
o dilate pupils for beauty (atropine)
mAChR Agonists
LIGAND Receptors
M1 M2 M3 M4 M5
Acetylcholine X X X X X
(ACh)
Carbachol X X X X X
Muscarine X X X X X
Oxotremorine X X X X X
Pilocarpin E X
mAChR Antagonists
LIGAND Receptors
M1 M2 M3 M4 M5
Atropine E X X X X X
Scopolamine X X X X X
Pirenzepine X
Gallamine X
4-DAMP X
Tropicamide X
3/26/09
Catecholamine biosynthesis
Tyr (tyrosine crosses BBB) TH (tyrosine hydroxylase) DOPA AAAKC
(alpha amino acid decarboxylase) or DOPA decarboxylase (DDC)
Dopamine (in the VTA and SN this is the end) but others continue using
dopamine Beta hydroxylase norepinephrine (adonergic) in adrenal
cortex it is converted into Epi (epinephrine) via PNMT
LDOPA when used to treat Parkinson’s it is used with Carbidopa (blocks TH)
so that tyr isn’t converted. Carbidopa doesn’t cross BBB. LDOPA is
transported into the brain slowly.
DA degradation
DA
Reuptake inhibitors
DAT NET SERT
(DA transports) (NE transporter) (5-HT transporter
Indatraline* (antidepressant)
cocaine
Bupropion (wellbutrin)*
Nomifensine (merital) Reboxetine*
Duloxetine (cymbalta) Atomoxetine**
Amphetamine Imipramine*
Amitriptyline*
Venlafaxine*
Clomipramine***
• *antidepressants
• ** ADHD
• *** anxiolytics
DA-specific neurotoxins
MPTP glial MAO-B MPP+ (shuts down kreb cycle in mitochondria)
6-OH-DA
1. Both MPP and 6OH DA are substrates for DAT
2. Both are then taken into mitochondria
3. Both block oxidative metabolism
4. Both kill DA neurons selectively and dose-dependently
5. Both produce behavioral effects mimicking parkinsonism
DAR types
Name D1 D2 D3 D4 D5
Synaptic Post- Pre- and Post- Post- Post-
location Post-
Alpha Gs Gi Gs
subunit
effector
Beta Decrease
gamma VDCC,
subunits VDKC,
effects CDKC
The ctx has D1-D5
Hypothalamus has D3 + D5
Corpus striatum has D1 + D2
DA agonists
Ligand DA receptor type Other catecholamine
receptors
D1 D2 D3 D4 D5 Alpha beta
Dopamine X X X X X X
Apomorphine X X X X X
Dihydrexidine XX X
bromocriptine X X X
Praminpexole X XX
Ropinirole X XX
DAR antagonists
Ligand DA receptor type
D1 D2 D3 D4 D5
Spiperone XXX XXX XX XX XX
Ecopipam X
Amisulpride XXX X
Chlorpromazine XX X X
*
Trifluoperazine* XX X X
Haloperidol* XX X X
Resperidone* XX X X
• out patient drugs
Neuroleptics vs. tricyclic antidepressants vs. Li+
3/31/09
Catecholamines – Norepinephrine (NE)
Uses/abuses of NE ligands
- Clinical
o Cardiac regulation (rhythm, rate, volume)
o Antihypertensive
o Bronchial dilation (asthma relief)
o Anti-depressant
o Anti-ADHD/ADD
o Anti-OCD
o Decongestant
- Recreational
o Hallucinogenic
o Amphetamine-like effects
Alpha 1 (α 1) Adrenoceptors
Name α 1A α 1B α 1D
Expresse CNS, Resistance CNS,
d in: heart, vessels, aorta,
(don’t need
liver, kidney, lung,
urogential spleen bladder
to know) smooth
muscle
Non- DA
selective NE
AGO EPI
Phenylephrine
Ephedrine, Pseudoephedrine
Selective Tetrahydr
AGO ozoline
Selective Niguldipin Cycloazosi
ANT e n
(don’t need 5- Spiperone
to know) methylura
padil
Non- Phentolamine
selective Prazosin
ANT
Suicide Phenoxybenzamine
ANT
G-protein Gq - ↑ IP3/DAG
Decongestants, eye drops (α 1 AGO)
Ephedrine
Pseudoephedrine
Phenylephrine (nyquil)
Tetrahydrozoline (eyedrops)
Alpha 2 (α 2) Adrenoceptors
Name α2A α2B α2C
Expresse CNS, Thalamus, CNS, lung
d in: Lung, liver,
vascular vascular,
muscle spleen
Function Autorecept Vasoconst Undeterimi
or; riction ned
Vasoconst
riction,
sedation,
analgesia,
anesthesia
Non- NE
selective EPI
AGO Clonidine
Selective LSD-25
partial
AGO
Nonselect Phentolamine
ive ANT Prazosin
Yohimbine
α Gi
-subunit
β-ϒ Inhibit VDCCs, activate CDKCs
subunits
Antihypertensive vasodilators (alpha ANT)
4/2/09
Indolaminergic transmitters – Serotonin (5-HT)
Peripheral 5HT
- first purified from blood plasma (serotonin): 1948 and first purified
from the brain in 1957
- total quantity of the body < 10 mg (5% of that in brain)
- Intestines 0 enterochromaffin cells enhance motility of 5HT4
- Blood vessels – platelets; vasoconstriction: 5HT1D
- Also a mitogen: enhances cell proliferation in muscle, liver but not in
the bone
5HT pathways: Raphe n. which are widely distributed from the pons
down the brainstem and project throughout the rest of the brain.
The largest are the dorsal and median Raphe n. They are pyramidal
neurons and they have afterhyperpolarization (modulated by
apamine). These neurons are important in the sleep/wake cycle.
They are almost completely silent when sleeping and active during
waking.
Hertogeneous 5HT fiber systems
- Doral Raphe n. has diffuse projections
- Median Raphe n. has specific projections
SERTs
- ATPase pumps protons into the vesicle
- SERTs pump 5HT and Na+ & Cl- into the vesicle and 5HT and K+ outside the vesicle
Pr
ot
ei
n
Anziolytic (5HT1a agonist) – buspirone
5-HT2Rs
5-HT2A 5- 5-HT2C
HT
2B
No 5HT
nse Quipazine
lect
ive
ago
nist
s
Par LSD-25 LSD-25
tial Psilocybin/p Psilocybin/
ago silocin psilocin
nist Pyschedelic Pyschedelic
s
phenylethyl phenylethyl
amines amines
Sel DMT agomelatin
ecti DOM (STP) e
ve
ago
nist
s
Sel Ketanserin Me ritanserin
ecti ter
gol
ve ine
ant
ago
nist
s
No Mesulergine
nse dibenzyline
lect
ive
ant
ago
nist
G- Gq
Pro
tei
n
Psychedelic effects mediated by 5HT2ARs
- competitive antagonists do not block psychedelic effects
5HT3Rs
5HT3Rs
Nonselective agonists 5HT
Quipazine
Selective agonists CBG
Selective antagonists Ondansetron (keeps you
from vomiting)
Zacopride
Mechansism Petameric cation channel
(weak selectivity for Na+)
Antiemetics (5HT3 antagonists) – used extensively to alleviate
nausea in chemotherapy
- ondansetron
- zacopride
- also used in IBS treatment
Melatonin
Serotonin 5HTNacetylase Nacetyl-5HT 5-OH-indole-OMT
melotonin (pineal gland) *just know that it is serotonin synthesizes
melatonin in pineal
REVIEW PERIOD
Synthesis and metabolism of the neurotransmitters
mGluR
Get the information off the website
- Three classes
o Class 1: mglu r1 mGluR5
o Class II: mGluR2 m GluR3
o Class II: mGlu
o Class I increase IP3 and Ca+
o Class II and III decrease cAMP
o Involved in perception of pain, affect and mood, learning and
memory, modulating activity of voltage dependent ion channels,
modulating
Dopamine
- reuptake inhibitors (prescribed as antidepressants)
o buproprion
o nomifensine
o indatreline
o mazindol
o amphetamine
- amphetamines and analogs
o amphetamines
o dextroamphetamine
o methamphetamine
o methylphendate
o Cocaine
o Phenmetrazine
- DA specific neurotoxins
o MPTP
o 6-OH-DA
Norepinephrine
- major source of NE in the brain – locus coeruleus
- peripheral release blockers
o quanathedine, guanadrel, bretylium
o CNS Ganglionic synapse NMJ
o Sympathetic NS
- Cental release blockers (cross BBB)
o Guanathedine, bretylium
- NE classes of receptors
o Alpha 1 accitvates Gq which increases PLC
o Alpha 2 – gi decresase cAMP
o Beta1 and beta 2 Gs increase cAMP
SSRIs
Antidepressants
Seratonin Hallucinogens
- DMT
- Psilboc
←
← 4/7/09
← Histamine (last of the biogenic amines)
←
← Peripheral HA
← - Inflamation (in mast cells): H1Rs
• orgasm
• allergy
• congestion
← - Digestion: H2Rs
• gastrin
• Parietal cells create gastric acid
← - Immune Response: H4Rs
• basophils
• neutrophils
• bone marrow
←
← HAminergic neurons: transport, synthesis, degradation
• L-amino acid transporter takes HA into the cell (AAAT)
• Histidine is converted by histidine decarboxylase (HD) into histamine and
transported into vesicles via Vesicular MonoAmine Transporter (VMAT).
• Histamine methyltransferase (HAMT) breaks down histamine into
telemethylhistamine
←
← CNS HA: Hypothalamic tuberomamillary nuclei* (TMN) project to the
rest of the body.
← *(right above the mamilary bodies)
←
← Tuberomamillary neurons (TMN
← - large soma, dendrites
HAR Types
Receptor H1 H2 H3 H4
g-protein Gq Gs Gi Gi
Neuronal Postsynaptic Postsynaptic Presynaptic postsynaptic -
location
Global Waking state; Waking state; Autoreceptor; ? -
Function arousal; appetite arousal regulate
suppression learning and transmission;
memory inhibit -waking
arousal
Other Mast cells Parietal cells Basophils;
Tissues neurophils;
bone
marrow;
smooth
muscle
Peripheral Inflammation; Acid release allergies
Function congestion;
orgasm
H3 is the only autoreceptor.
- If you block the receptor you increase firing rate of the postsynaptic neuron.
- H3 presynaptic block of Voltage Dependent Ca Channels.
- An AGO will decrease the inward current through VDCCs.
- Autoreceptors act like this
Uses/potentials of HA ligands
- Peripheral
o Allergy treatments (peripheral H1 ANT)
o Anti-congestive (peripheral H1 ANT)
o Anti-inflammatory (peripheral H1 ANT)
o Antacids (peripheral H2 ANT) *not really antiacids but go the problem of the
acid.
- Central
o Anti-emetics/anti-vertigo (H1 ANT)
o Hibernation, sleep (H1 ANT)
o Stimulants (H3 ANT)
o Alzheimer’s therapies (H3 ANT)
o Nootropics (H3 ANT)
o ADD therapies (H3 ANT)
o Anti-obesity treatments (H3 ANT)
HA Agonists
Competitive HAR
Agonist H1 H2 H3 H4
Histamine (HA) X X X X
Dimaprit X
Proxyfan (partial) X
Imetit X X
Steroid receptors:
- Intracellular, not membrane bound
- Hormones have receptors in the cytoplasm and then its translocated into the steroid
receptor complex to the nucleus. Binding of complex to DNA regulatory site.
Transcription then translation
1. Ligand binding
1.5 HSP (heat-shock protein) release
2. Translocation via nuclear pore complex
3. Dimerization and DNA binding
4. Gene transcription
5. Also includes RNA transport, insertion in ER, translocation into protein, and possible
post-translation protein modification.
Estrone
Antagonists Tamoxifen Flutamide Mifepristone Spironolactone
Agonist Regulate Maintenance of Enhance bone Increase hepatic Na+ retention
hormone sex drive Ca2+ retention gluconeogenesis
Effects /K_excretion by
secretion
Enhance bone Stabilize uterine Increase protein
Regulate kidney distal tubules
Ca2+ retention proliferation catabolism,
cholesterol
Increase lipid Stabilize lipid glycogenolysis
metabolism
protein metabolism Increase BP
Increase
synthesis Increase HR
lipid protein
Maintain Immunosuppressio
synthesis
neural n
Breast tissue
plasticity
stimulation
Maintain
neural
plasticity
Anti-estrogens
ER-antagonists – used in treatment of breast cancers to block proliferation of
estrogen-sensitive tumor cells
Tamoxifen
Clomiphene
Or aromatase inhibitor – anastrozole
Anti-progestins
Progesterone Rs antagonists are used as arbortifactants to disrupt
maintenance of uterine endometrial lining to block fertilized egg
implantation. Mifespristone (RU486) morning after pill prevents egg
implantation
Metabolites of Androgens
Active Inactive
DHT (another one too) Don’t need to know
Testosterone
Anti- Androgens
- competitive ANT
o flutamide
- alpha-recutase inhibitor
o finasteride
used for: treatment of sex offenders, prostate cancer, male-pattern baldness (vs minoxidil
rogaine K-ATPactivator)
4/21/09
Anterograde amnesia
Euphoria Delta
Memory impairment
Analgesia
Sedation
Alcoholism
- tolerance tends to develop rapidly
- dependence tends to develop more slowly
- well defined genetics links (dependence prone)
- gradual development of reverse tolerance (impaired metabolism)(
- multiple motor effects, some of which habituate
- Korsakoffs, other vitamin deficiency effects
- Social issues, socieoeconomic outcasting
- Societal role in definitions of “problem dringking, binge drinking partying
- Recidivism high, long-term prognosis poor
Old “membrane fluidity” theories – they thought the channels changed shape of all the
proteins
Tandem-pore K+ channels
Name Tamdem poore
Ca 2 sensitivity Insensitive
Ligand seneitivie ?
Activation -60mV/-40mV
Inactiavition Slow (s)
Actiavatiors Isoflurane
Sevoflurane
Blockers Unknown
Hyperbaric Oxygen as an anesthetic, toxin
4/23/09
NSAIDs, peptides and alkaloids – opiates, opioids, and other analgesics
Next Thursday is the review for the final exam.
Analgesics (“pain-killers”)
- Analgesia = relief of pain
o Surgical
o Acute
o Chronic
o Phantom
- Analgesic formulations
o Short-acting
o Intermediate
o Long-acting
1897 Bayer Ad
Respiratory-depression
ANT Cyprodime Naltriben
(specific)
ANT Naloxone
Naltrexone
Diprenophine
G protein Gi/Go
Stucture of endogenous ligands
Modified opiates
- diacetylmorphine (heroin)
- hydromorphone (dilaudid)
- oxycodone (percodan, oxycontin)
- hydrocodone (vicodin)
Addiction/dependence
- Physical
o Development of tolerance
o Other kinases upregulated to compensate for PKA suppression
o Rate of development differs by cellular phenotype
- Psychological
o Need for hedonic effects (which decline)
o Need to avoid withdrawal symptoms (increases)
o Sedation soothes anxieties re. addiction
Withdrawal
- Early symptoms
o Watery eyes, runny noes
o Yawning, no appetite
o Anxiety, irritability
o Restlessness, insomnia
o Rapid increase of AC activity
Methadone – agonist but does not have pleasurable effects like heroin
Overdose
- Initial symptoms
o Slow, shallow breathing
o Cognitive impairment
o Constricted pupils
o Severe drowsiness
o Cold, clammy skin
4/28/09
Drugs of abuse – illicit or illegal ligands
- Depressants
o Barbiturates/BDZs
o Opiates
o PCP/ketamine
- Hallucinogens
o Marijuana/hashish
o Peyote
o LSD
o PCP/ketamine
o Psilocybin
o Designer drugs
- Anabolic steroids
o Androgens
Sources of illicit drugs
- synthesis
o diversion from regulated sources
o extraction/modify/purify
- Nature
Drug Enforcement
- Federal (sets the standards others follow) Under FBI
o DEA (justice): concentrates on trafficking (international and interstate), diversion,
elimination of foreign growers
o AFT (Treasury): concentrates on domestic production, growers, theoretical “revenue”
sources
- State
o DPS: involves all levels, including low-level dealers and users
- County
o Sheriff: all levels, including low-level dealers and users
- Local
o Police: all levels, including low-level dealers and users
o
schedules
Variability in enforcement I
- stimulants
o caffeine – none
o nicotine – no sales to minors, smoking bans
o cocaine – schedule II
o amphetamines – schedule II
o designer drugs – schedule I
- depressants
o EtOH – no sales to minors; driving prohibitions
o Opiates – schedule I, II, III, IV, or V
o Barbiturates – Schedule II, III, or IV
o BDZs – schedule IV
o Methaqualone – schedule I
- Hallucinogens
o Designer drugs – Schedule I
o LSD – Schedule I
o Pyote – Schedule I
o Psilocybin – Schedule I
o Marijuana – Schedule I
o PCP – Schedule I
o Ketamine – Schedule III
- Anabolic steroids – Schedule III
Stimulants
- health risks
o sudden arrythmias, etc. leading to cardiac failure risk of acute psychosis with
high doses/chronic use perceived subjective superiority in performance.
DOES NOT match objective measure
- Physical dependence
o Strong risk
o Once developed, physical withdrawal begins within hours after last does
o Withdrawal less severe than opiates
- Psychological dependence
o Stong risk
o Recidivism high for former users (as high or higher than for opiates)
Hallucinogens
- Health Risks
o Multiple reports of mental health problems (can unmask borderline or
developing problems)
o Bad trips, flashbacks
o Substantial risk of obtaining high dose/erroneous substance
- Physical dependence
o None substantiatesd
- Psychological dependence
o Can develop for piperidine dirivitives (PCP, ketamine, etc.) unlikely for others
- Footnote:
o Original medical model to manage hallucinogenic use suggested
recreational/spiritual clinics, with controlled set, setting and dose of known
compounds
o Cf. early works of Richard Alpert, Timothy Leary, Sashatchewan psychiatric
model, et al. treatment of alcoholism, etc.
Opiates
- Health risks
o Overdoes – potentially fatal coma, respiratory depression, emesis
o HIV and other serology – related risks of drug injection
o Malnutrition possible due to severe appetite suppression (coupled with GI
motility reduction)
o Issues related to contaminants/cuts/dose and purity
o Withdrawal related to categories below
- Physical dependence
o Strong risk
o Once developed, physical withdrawal begins within hours after last dose
- Psychological dependence
o Strong risk
o Recidivism high for former users
Other depressants (ETOH, BDZs, barbiturates)
- Health Risks
o Overdose – potentially fatal coma, respiratory depression, emesis (vomiting)
o Issues related to contaminants/cuts/dose and purity
- Physical dependence
o Strong risk
o Once developed, physical withdrawal begins within hours after last dose
o Withdrawal less severe than for opiates
o Psychological dependence
o Strong risk
o Recidivism high for former users (as high or higher than for opiates)
Cannaboid receptors
Receptor CB1 CB2
Tissue expressing CNS (hippocampus; ctx; Immune system cells
basal ganglia; cblm) rarer in
periphery ()lung; vascular
tissue; testis; uterus
Endogenous AGO Anandamide
Selective AGO JWH-015
Hallucinogenic amphetamines:
- DMO= STP= dimethoxyamphetamine
- MDA
Anabolic steroids
- Health risks
o Immunosuppressant
o Cardiac hypertrophy, leading to cardiac failure
o Acceleration of male balding
o Induction of prostate cancer and other tumors
o Risk of acute psychosis with high doses/chronic use
- Physical dependence
o Not well studied; likely
- Psychological dependence
o Considerable risk
******Final Review******
A
04/05/2009 19:59:00