Mnpc Substance Abuse

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Classes of psychomimetic agents

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Lysergic acid derivatives
phenylethylamine (eg amphetamine)
N-methylll-3-piperdyl benzilate
PCP (phenylcyclohexylpiperidine)
indolealkylamine (eg serotonin)
cannabinoids

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2 classifications of psychomimetic agents

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classical hallucinogen: meet hollister def, molec def of binding serotonin 5-ht2 receps, behavioral def of DoM recognition

dissociative: reduces/blocks signals to "the conscious mind" from other parts of the brain. produces feelings of detachment from the env't; inhibits sensations from physical senses.

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Drug discrimination paradigm

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used to study a wide variety of psychoactive agents
does not represent a model of psychotomimetic activity since can't tell if animal is hallucinating
technique has general applicability and has been used to study stimulants, barbs, opiates, anxiolytics etc

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Terminal amine characteristic required for amphetamine-like action

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N-Me

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terminal amine characteristic required for DOM-like action

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NH2

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Chiral center required for amphetamine action

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S (+)

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chiral center needed for dom-like action

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R (-)

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Aromatic substitution required for amphetamine like action

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unsubstituted

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aromatic substitution preferred for dom-like action

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2,5 dimethyl-substitution preferred
4 substitution further modulates activity.

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Phenylisopropylamine stimulants
SAR on aromatic ring

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amphetamine related (Includes PCA, fenfluramine, amphetamine)
electron-withdrawing groups can afford 5-HT release activity. other substitutions reduce amphetamine stimulant activity.

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phenylisopropylamine (amphetamine relateds) SAR on amine substitution

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Primary most potent
Exception: Methamphetamine (NHR) likely 2-3 times MORE potent than parent.

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Most widely abused synthetic

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methamphetamine (phenylisopropylamine)

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SAR of alpha substituents on phenylisopropylamines (amphetamine related)

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Phenylethylamine lacks cental stimulant activity (no alpha sub). Homologation of alpha Me to a-ethyl or a-n-propyl results in a decrease/loss of central stimulant activity.
**Preserving chirality, S-enantiomer several-fold more potent.

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phenylisopropylamines (amphetamine related) SAR of b-substituents

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much less known. eg ephedrine and pseudoephedrine

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MoA: Amphetamine

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indirect acting dopaminergic and noradrenergic (also serotonergic) agonist.
Binds and blocks DAT and NET, so can't clear from synapse. Also release of NTM thru transporters (conformational change induced causing NTM release)

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Cocaine and related agents!
chemical name
origin
other roles

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Cocaine: 2R-carbomethoxy-3S-benzyloxy-1R-tropane
Erythroxylon coca-So.America
Vasoconstrictor & local anesthetic

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Cocaine et al MoA

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BLOCK reuptake of NE, serotonin, DA
Does NOT induce additional release of NTM

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Components of autonomic nervous system

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PS (SLUDD)
Sympathetic

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Components of peripheral nervous system

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autonomic (PS/S)
somatic

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Ach

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exhaustively studied
NTM for many diff neurons
KNOW structure: choline + acetyl.

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Cholinergic fibers

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released by pre- and post-ganglionic fibers

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Ach receptors: cholinergic receptor classification

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Muscarinic: muscarine--naturally-occurring alkaloid (5-member ring)
Nicotinic: nicotine--5-member attached to 6-member

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Use of muscarinic agonists?

antagonists?

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reestablish SM tone following surgery

antispasmodics (overactive bladder, GI spasms)

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Use of nicotinic agonists?

antagonists?

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tx Myasthenia gravis

muscle relaxant (surgical)

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Muscarinic receptor characteristics

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esteratic site for acetyl portion of Ach to bind

anionic site for choline portion to bind. Aspartate represents a potential anionic site.

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Early studies of Muscarinic receptor SAR could not explain:

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2 grps on N must be Me
Known stereochemical preference
Ing's Rule of 5: All potent cholinergic AGONISTS have only 5 atoms between N and terminal H

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More modern studies of muscarinic receptors

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Computer-assisted modeling has refinded models, including showing arrangement of helical bundles and binding sites.

GPCR Crystal structures(2000 Rhodopsin, 2007 b-adrenergic receptors, 2012 activated receptors) have given insight into structure-fxn.

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Crystal structure of Rhodopsin

Crystal structure of human b2-adrenergic

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mj discovery by Palczewski et al: GPCR

mj discovery by Rasmussen, SG et al.: GPCR

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Effects of Muscarinic receptor

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Adenylate cyclase: activation of MAchR--> INHIBIT adenylate cyclase --> reduction of cAMP cellular levels

Phospholipase C: Activation of receptor activates PLC--> incr DAG, inc IP3 --> incr intracellular Ca2+ --> activation of PKC

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Pirenzepine

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blocked gastric acid secretion but not the effect of muscarinic agonists
This led to M1 through M5

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mAchRs are G-protein coupled

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heterotrimeric protein that associates with an effector protein that leads to cAMP, Ca2+, IP, and DAG.
Different G proteins determine fxn.

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M 1,3,5: couple to

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Gq

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Muscarinic receptors 2 and 4 couple to

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Gi/Go...inhibit AC and v-gated calcium channels, activate G protein-coupled inwardly-rectifying potassium channels
M2: autonomic nerve terminals, CNS, Heart, MS
M4: CNS

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Model of Ach interaction with Muscarinic M1 receptors
which 3 amino acids are included in the receptor?

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Ach fits in bundle of 7 helices which include aspartate, tyrosine, threonine.

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G protein cycle

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when Ach binds, GDP is exchanged for GTP, which causes the beta and gamma subunit to dissociate from the alpha and cause downstream effects. the alpha subunit then has GTPase activity which leads to the beta and gamma rebinding and the process starting over.

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M1 receptors:

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"neural": abundance in cerebral cortex, hippocampus, striatum.
implicated in alzheimer's--thought to be involved in learning and memory
Found in autonomic ganglia, enteric nerves, salivary and gastric glands. Agonists of M1 show greatest promise for treating cholinergic deficit in alzheimers.

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M2 receptors:

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Mainly in heart: negative chronotropic and inotropic
SM: stim contraction
Activation of M2 autoreceptors on nerve terminals affords neural inhibition by decreasing Ach release.

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M3 receptors:

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Mainly SM and glands-->contraction and secretion
antagonists for overactive bladder.
fxn in CNS to decrease NTM release.

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M4 receptors:

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striatum and basal forebrain: decrease NTM release in both CNS and perifery.
Activation in SM and secretory glands leads to inhibition of K and Ca channels.

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NicotinicAchRs are found:

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skeletal NMJs
Adrenal medulla
Antonomic ganglia (Regulate sweat glands, cardiac and SM)

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Nicotinic Ach R's

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Ligand-gated ion channels
GABA-A and glycine receptors
Ach acts as gatekeeper
When Ach binds, allows passage of ions--mainly K and Na.

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Nicotinic receptors

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pentameric transmembrane proteins comprised of alpha, beta, gamma/ epsilon in mature muscle endplates, and delta subunits.

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Nicotinic receptor subunit combinations

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Diverse: may not have epsilon or delta etc...may only be comprised of subtypes of alpha etc. Just as long as there are 5 total.

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Arrangement of NAchRs

Where does Ach bind?

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4 transmembrane spanning helices per bundle * 5 bundles

Ach binds alpha-delta & alpha-gamma interface.

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Remember! NAchR ligand-gated ion channels are often sensitive to :

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certain toxins such as bungarotoxin (esp those in the CNS)

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Key difference between reversible and irreversible AchEI's:

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Aging-left with a charged species with not good leaving group from serine. Enzyme cannot regenerate.

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Irreversible AchEI's

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Sarin
Echothiophate for glaucoma and strabismus
"thion's"

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SAR: MAchR Antagonist

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Most potent have 2 lipophilic ring substit's on C alpha to carbonyl group.
R1&2 should be carbocyclic or heterocyclic rings for max potency
Rings can be identical, but most potent untags have 1 aromatic ring and 1 ring w/ just 1 dbl bond.
Rings can be fused.
R3 can be proton, hydroxyl, or methyl ether. proton is less potent.
X=ester or ether. ester more potent.
N-substitution: 4' ammonium=most potent. tertiary still tolerated.
Most potent compounds have ethylene linker, but Ing's rule of 5 does not apply.

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NAchR antag: competitive or non-competitive?

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competitive. NM BLOCKERS.

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what would you use for a surgical muscle relaxant?

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NAchR antag eg tubocurarine

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adjuvant to gaseous anesthesia?

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NAchR antag eg tubocurarine

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What agent reduces the depth of anesthesia necessary?

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NAchR antag eg tubocurarine

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Depolarizing NMJ Blocker
Examples:

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leads to histamine release, flushing, pulmonary sxs such as bronchospasm, wheezing, and hypotension.
Decamethonium bromide, Succinylcholine chloride