Mnpc Iii Exam 3- Cholinergic Drugs

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components of PNS (2)

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autonomic (sympa, parasympa)
somatic

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acetylcholine properties (2)

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most exhaustively studied mammal system

functions as NT for many different neurons

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acetylcholine can be released by...

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pre and post ganglionic fibers

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types of Ach receptors (2)

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muscarinic

nicotinic

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muscarine

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naturally occuring alkaloid (molecule with basic nitrogen

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chemical compounds that stimulate the parasympathetic system are called...(2)

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cholinomimetics or parasympathomimetics

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2 possible ways parasympathomimetics can work

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bind and activate receptors

or block AchE

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2 names of cholinergic antagonists

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cholinolytic
parasympatholytic

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muscarine

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Back 10

nicotine

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acetylcholine

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muscarinic agonists- what are they used for

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reestablish smooth muscle tone following surgery

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nicotinic agonists- what are they used for

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to treat myasthenia gravis

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muscarinic antagonists what are they used for

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antispasmodics (overactive bladder, GI spasms, etc)

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anticholinergic - used for what

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muscle relaxant (surgery)

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early SAR model of Ach binding to muscarinic receptor

(2)

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imagined to have 2 sites on the receptor:
esteratic and anionic site

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describe the esteratic and anionic site of muscarinic receptor of early Ach binding SAR model

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esteratic reacts with O of ester group on Ach
aspartate sits in anionic pocket and binds with quaternary amine

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what was wrong with the early Ach binding model? (other SAR it could not explain) (4)

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2 groups on the amine must be methyl groups
there is a known stereochemical preference
has no chirality
Ing's rule of five

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what is ing's rule of five

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all potent cholinergic agonists have only 5 atoms between nitrogen and terminal hydrogens (not counting the O bound to carbonyl)

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2 more modern studies regarding SAR of Ach binding

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computer assisted modeling has refined models to show arrangement of helical bundles and binding sites

GPCR crystal structures have been realized

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2 different downstream ...effectors...of M receptors

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adenylate cyclase
phospholipase C

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M receptor activation and what happens with AC (2)

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activation of muscarinic Ach receptor causes inhibition of adenylate cyclase

this causes reduction in cAMP in cell

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M receptor activation and what happens with PLC (3 steps)

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PLC activation -->cleaves lipid into DAG and IP3
these go on to increase intracellular Ca++
Ca++ activates PKC

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pirenzipine- what is it?

significance?

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compound found that blocked gastric acid secretion, but did not block effect of muscarinic agonists

discovery led to M receptor subtypes (1-5)

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structure of pirenzipine?

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---

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mAchR- receptor type

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GPCRs

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structure of GPCR (2)

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7 TM protein
heterotrimeric (stuck to alpha, beta, gamma subunits)

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M receptors coupled to Gq

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odd letters
M1,3,5

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M receptors coupled to Gi/o

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M2,4

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M1 receptors- location (5)

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CNS, gastric, salivary, autonomic ganglia, enteric nerves

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M1,3,5 - describe pathway of activation

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Gq-->
PLC activation
increases IP3/DAG leading to increased IC calcium and PKC activation-->depolarization

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M3 receptors- location (4)

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CNS, smooth muscle, glands, heart

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M5 receptors location (2)

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low lvls in CNS/periphery
mostly in DA neurons of substantia nigra/vta

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M2 receptors Location (4)

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autonomic nerve terminals
CNS
heart- lower rate
smooth muscle- contract

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M4 receptors location

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CNS

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3 binding sites of muscarinic receptors

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Asp (- charge attracts quat amine), Tyr, Thr

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G protein process of signalling (5 steps)

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1) Aby bound to GDP
2) exchange factor switches GDP for GTP upon binding of Ach
3) b-y dissociates to activate stuff downstream
4) alpha has GTPase activity and hydrolyzes GTP to GDP
5) reassociates with By

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3 specific brain areas where M1 is found

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cerebral cortex
hippocampus
striatum

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M1 receptor properties (2)

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sometimes termed "neural" because abundant in brain

implicated in alzheimer's (function/memory/learning)

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M1 agonists- greatest use

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alzheimer's

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4 characteristics of M2 receptors
found where, effects/roles (3)

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found in abundance in the heart

negative chronotropic and inotropic actions

contract smooth muscle

autoreceptors

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M2 autoreceptors- location and what they does

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located on nerve terminals

affords neural inhibition by decreasing Ach release

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M3 receptors- found in abundance where 3)

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found in abundance in smooth muscle and glands

CNS

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M3 receptor stimulation leads to... (2)

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stimulation leads to contraction and secretion

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M3 receptor drugs

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antagonists- for overactive bladder

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M3 role in CNS

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decrease NT release

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M4 receptors- found in abundance where? (2)

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found in striatum and basal forebrain

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roles of M4 receptor (what happens when it activates) (2)

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activation in smooth muscle/secretory glands leads to inhibition of K+/Ca++ channels

decreases transmitter release in CNS/periphery

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M5 receptor role

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may regulate DA release in CNS

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3 places that NAchR are found

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skeletal NMJ
adrenal medulla
autonomic ganglia

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NAchR type of channel

related to what types of receptors

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ligand gated ion channel

closely related to ion channels like GABAa, glycine, etc

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NAchR - how they work /are activated

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unlike in muscarinic receptors with their secondary messenger pathways, it acts more like a gatekeeper. when it is bound, it allows passage of ions (K+/Na+)

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NAchR structure (2)

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pentameric transmembrane proteins
can be made up of a, b, gamma/epsilon, delta

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NAchR subunits- alpha, gamma, epsilon- explain significance of each

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alpha1 is only one in muscle
gamma- mostly in development only
epsilon- if receptor is mature

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typical subunit arrangements of NAhR (neuronal) 2

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(a4)2(b3)3

homomeric- a7-10 (can consist of any 5 of these units)