colinergici, anticolinergici &...

COLINERGICI, ANTICOLINERGICI & COLINERGICI, ANTICOLINERGICI & ANTICOLINESTERASICIANTICOLINESTERASICI

S.MORO – CFTII 2016/2017MM S Confidential and Property of ©2012 Molecular Modeling Section

Dept. Pharmaceutical and Pharmacological Sciences –University of Padova - Italy

Parte IIParte II

12. Cholinergic receptors 12. Cholinergic receptors

Receptor typesReceptor types•• Not all cholinergic receptors are identicalNot all cholinergic receptors are identical•• Two types of cholinergic receptor Two types of cholinergic receptor --nicotinicnicotinic and and muscarinicmuscarinic•• Named after natural products showing receptor selectivityNamed after natural products showing receptor selectivity



Ligand-gated ion channels(ionotropic receptors)

G protein-coupled receptors(metabotropic receptors)

12. Cholinergic Antagonists (Muscarinic receptor)12. Cholinergic Antagonists (Muscarinic receptor)

•• Drugs which bind to cholinergic receptor but do not activate itDrugs which bind to cholinergic receptor but do not activate it•• Prevent acetylcholine from bindingPrevent acetylcholine from binding•• Opposite clinical effect to agonists Opposite clinical effect to agonists -- lower activity of lower activity of

acetylcholineacetylcholine



Postsynapticnerve

Ach

Antagonist

Ach

Postsynapticnerve

Ach


Clinical EffectsClinical Effects•• Decrease of saliva and gastric secretionsDecrease of saliva and gastric secretions•• Relaxation of smooth muscle Relaxation of smooth muscle •• Decrease in motility of GIT and urinary tractDecrease in motility of GIT and urinary tract•• Dilation of pupilsDilation of pupils

UsesUses



UsesUses•• Shutting down digestion for surgeryShutting down digestion for surgery•• Ophthalmic examinationsOphthalmic examinations•• Relief of peptic ulcersRelief of peptic ulcers•• Treatment of Parkinson’s DiseaseTreatment of Parkinson’s Disease•• Anticholinesterase poisoningAnticholinesterase poisoning•• Motion sicknessMotion sickness

From agonist to antagonist: From agonist to antagonist:

AcetoxyAcetoxy

EthyleneEthylenebridgebridge

44oo NitrogenNitrogen

Me ONMe3

O

AcetoxyAcetoxy

EthyleneEthylenebridgebridge

NitrogenNitrogen

Me ONMe3

O

DoDo youyou remember?remember?



From agonist to antagonist: From agonist to antagonist:

CH3 O

OO

O

Agonist Antagonist(mainly muscarinic)

12.1 Atropine12.1 Atropine


α-tropanol

)

NCH3



Tropic acid

Atropa Belladonna (Solanaceae)

O

O

CH2OHH

Tropane derivativesTropane derivatives

1 2

345

6

7

8

8-methyl-8-azabicyclo[3.2.1]octane



Atropine

(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate

α

methyl (1R,2R,3S,5S)-3- (benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate

Cocaine

β

Tropane derivativesTropane derivatives

Al(isoBut)2H Na/Hg (2%)

Mother nature…



Al(isoBut)2H

THF

95 : 5

H2O (H2SO4, pH = 3.4)

25 : 75

versus the human chemistry!

12.1 Atropine… or D/L Hyscymine12.1 Atropine… or D/L Hyscymine

easily racemised


N

O

CH2OH

CH3

H

*



O

*



L = 15.6 ÅVol ≅ 290 Å3

log P = 1.8MW = 289.4PSA ≅ 50Å2

eq



PSA ≅ 50Å2

O + N = 4pKa = 9.4

Ep (eq) = 47.9 kcal/mol

Ep (ax) = 49.6 kcal/mol

ax


•• RacemicRacemicform of form of hyoscyaminehyoscyamine((RR form) form)


N

O

O

CH2OH

CH3

H



•• RacemicRacemicform of form of hyoscyaminehyoscyamine((RR form) form) •• Source Source -- roots of belladonna (1831) (roots of belladonna (1831) (AtropaAtropa BelladonnaBelladonna))•• Used as a poisonUsed as a poison•• Used as a medicine Used as a medicine

decreases GIT motility decreases GIT motility antidote for antidote for anticholinesteraseanticholinesterase poisoningpoisoning

resuscitationresuscitationdilation of eye pupilsdilation of eye pupils

•• CNS side effects CNS side effects -- hallucinationshallucinations



N

O

O

CH2OH

CH3

H

A common mnemonic used to describe the physiologic manifestations of Atropine



A common mnemonic used to describe the physiologic manifestations of Atropineoverdose is:

hot as a hare, blind as a bat, dry as a bone, red a s a beet, and mad as a hatter !

These associations reflect the specific changes of warm, dry skin from decreasedsweating, blurry vision, decreased sweating/lacrimation, vasodilation, and centralnervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms isknown as anticholinergic toxidrome , and may also be caused by other drugs withanticholinergic effects, such as scopolamine, diphenhydramine, phenothiazineantipsychotics and benztropine.



N

O

O

CH2OH

CH3

H

Resuscitation!



Resuscitation!The action of this drug is to block the effect of the vagus nerve on the heart. This nerve normallyslows heart rate and, during cardiac arrest, is a common cause of asytole. Atropine also acts on theconduction system of the heart and accelerates the transmission of electrical impulses throughcardiac tissue.In cardiac arrest it is given to reverse asystole and severe bradycardia. The Resuscitation Councilrecommends that atropine be given for pulseless electrical activity with a rate of less than 60 beatsper minute or in complete asystole.This drug should be administered intravenously and the dose depends on the heart rhythm. Forbradycardia a dose of 0.5mg should be given and repeated every five minutes until a satisfactoryheart rate is achieved. In asystole a single dose of 3mg should be given and this should not berepeated unless the cardiac rhythm changes to bradycardia or pulseless electrical activity.



N

O

O

CH2OH

CH3

H



TheThe eyeseyes don’tdon’t lie!!!lie!!!



N

O

CH2OH

CH3

H

12.3 Comparison of atropine with acetylcholine12.3 Comparison of atropine with acetylcholine

CO CH3

NMe3

CH2CH2


anti conformation is fixed!



O

•• Relative positions of ester and nitrogen similar in both moleculesRelative positions of ester and nitrogen similar in both molecules•• Nitrogen in atropine is ionisedNitrogen in atropine is ionised•• Amine and ester are important binding groups (ionic + HAmine and ester are important binding groups (ionic + H--bonds)bonds)•• Aromatic ring of atropine is an extra binding group (vdW) Aromatic ring of atropine is an extra binding group (vdW) •• Atropine binds with a different induced fit Atropine binds with a different induced fit -- no activationno activation•• Atropine binds more strongly than acetylcholineAtropine binds more strongly than acetylcholine

O

- H+

+ H+logP=1.8

N

O

O

CH2OH

CH3

H

H+ N

O

O

CH2OH

CH3

H

Pharmacodynamics versus Pharmacokinetics:Pharmacodynamics versus Pharmacokinetics:



12.2 Hyoscine (scopolamine)12.2 Hyoscine (scopolamine)

N

H

Me




*

H

OC

O

CH

CH2OHO

H

H

Scopolia Japonica (Solanaceae)

epoxide


*

N

H

OC

O

Me

CH

CH2OHO

H

H




•• It is mostly a M1 muscarinic antagonistIt is mostly a M1 muscarinic antagonist•• Treatment of nausea and motion sickness (Treatment of nausea and motion sickness (transdermal routetransdermal route).).•• To reduce motility and secretions in the GI tractTo reduce motility and secretions in the GI tract.•• Treatment of intestinal cramping.Treatment of intestinal cramping.•• AsAs anan adjunctadjunct toto opioidopioid analgesia,analgesia, suchsuch asas thethe productproduct TwilightTwilight SleepSleep whichwhich containedcontained

morphinemorphine andand scopolaminescopolamine.. ThisThis combinationcombination inducesinduces aa semisemi--narcoticnarcotic statestate whichwhichproducesproduces thethe experienceexperience ofof childbirthchildbirth withoutwithout pain,pain, oror withoutwithout thethe memorymemory ofof painpain.. It isnow merely a chapter in the past history of obstetrics.


N

Me


NCH3

CH3

pKa = 9.7 pKa = 7.7



*

H

OC

O

CH

CH2OHO

H

H

O

O

CH2OHH

AdenylateAdenylateCyclaseCyclase GGssATP

cAMP

beta 2 adrenergic receptorH2 histamine receptorEndothelin receptors

M1 muscarinic receptorH1 histamine receptorOxytocin receptorP2Y purinerig receptor

IP3

PKCPKCDAG

GGqq

stimulatestimulate

PLCPLC

stimulatestimulate

CaCa2+2+

PKAPKA

Smooth muscle signal trasduction:Smooth muscle signal trasduction:



PCaCa2+2+

CaCa2+2+

CaCa2+2+

CaCa2+2+

PER

CaCa+2+2/calmodulin/calmodulin

MLCKMLCK+ -

myosin light chain kinase

myosinmyosin

P P

myosinmyosinCONTRACTION RELAXATIONactin

MLCPMLCPmyosin light chain phosphatase

P

IP3

CaCa2+2+

CaCa2+2+

PKAPKA

CaCa2+2+

CaCa2+2+

PER

CaCa+2+2/calmodulin/calmodulin

MLCKMLCK+ -

myosin light chain kinase

myosinmyosin

P P

myosinmyosinCONTRACTION RELAXATIONactin



MLCPMLCP

myosin light chain phosphatase

locally produced NO

soluble guanylyl cyclasesoluble guanylyl cyclase

GTPcGMP

cGMP-dependent protein kinase

5’-GMP

PDEPDE--55

Sildenafil(Viagra®)

-

Sildenafil(Viagra®)

log P = 1.9MW = 474.5PSA ≅ 110Å2



PDB code: 1UDT

The mechanism of action of Sildenafil involves the protection of cyclic guanosine monophosphate(cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpuscavernosum, leading to smooth muscle relaxation (vasodilatation) of the intimal cushions of thehelicinearteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into thespongy tissue of the penis, causing an erection.Other drugs that operate by the same mechanism includeTadalafil (Cialis) and Vardenafil (Levitra).Sildenafil is metabolized by liver enzymes and excreted by both the liver and kidneys.

PSA ≅ 110Å2

O + N = 10pKa = 8.7

ToTo crosscross…… oror notnot toto cross,cross, thisthis isis thethe dilemma!dilemma!

N

O

O

CH2OH

CH3

H

H+



ToTo crosscross…… oror notnot toto cross,cross, thisthis isis thethe dilemma!dilemma!

N

O

O

CH2OH

CH3

H

H+



without peripheral and SNC side effects!!!

12.4 The first good idea: the analogues of atropine12.4 The first good idea: the analogues of atropine


N

O

CH2OH

CH3

H

N

CH2OH

CH3

H

CH3

+

NO3-



•• Analogues are fully ionised Analogues are fully ionised •• Analogues unable to cross membranes including BBBAnalogues unable to cross membranes including BBB•• No CNS side effectsNo CNS side effects

Atropine methonitrate

O

O

O

O

12.4 The quaternary nitrogen analogues of atropine12.4 The quaternary nitrogen analogues of atropine

N

H

OC

CH3

CH

CH2OH

H3CNO3

N

H

OC

CH(CH3)2

CH

CH2OH

H3C

Br




Atropine methonitrate

O

Ipratropium

O

Oral administration:1. treat pain and discomfort

caused by abdominalcramps, or otherspasmodic activity in thedigestive system.

Inhalation administration:1. treat and prevent minor and

moderate bronchial asthma;2. treat of chronic obstructive

pulmonary disease (COPD).3. It is also combined with

Salbutamol (beta2 adrenergicagonist) for the management ofCOPD and asthma.

12.4 The most famous quaternary nitrogen analogue!12.4 The most famous quaternary nitrogen analogue!


Butylscopolamine(Buscopan®)

N

O

CH2OHHO

CH3

Br -

+



•• ButylscopolamineButylscopolamineisis usedused toto treattreat painpain andand discomfortdiscomfort causedcausedbyby abdominalabdominal cramps,cramps, menstrualmenstrual cramps,cramps, oror otherother spasmodicspasmodicactivityactivity inin thethe digestivedigestive systemsystem.. ItIt isis notnot anan analgesicanalgesic inin thethenormalnormal sense,sense, sincesince itit doesn'tdoesn't 'mask''mask' oror 'cover'cover over'over' thethe pain,pain, butbutratherrather worksworks toto preventprevent painfulpainful crampscramps andand spasmsspasms fromfromoccurringoccurring inin thethe firstfirst placeplace..

O

MatherMather naturenature……

Duboisia and the development of Buscopan®In the search for a safe and effective treatment for the pain of abdominal cramps,Boehringer Ingelheim learnt from the healing arts of some of the world's oldestcultures. Ancient Hindu physicians in India knew of the antispasmodic effects of arelative of Duboisia: the plant Datura. Today, the Buscopan® story starts in Ingelheim,Germany, where elite Duboisia plants are grown in greenhouses. These plants arebred to be resistant against nematodes and beetles. The best seeds are harvested and



bred to be resistant against nematodes and beetles. The best seeds are harvested andthen delivered to the company´s plantations in South America and Australia for furtheron-site selection. Here, the shrubs grow on a large scale. The pharmaceuticallyimportant alkaloid scopolamine which is contained in the dried leaves and stalks isisolated and purified. Finally, the active precursor substance scopolamine is convertedin a single chemical process into hyoscine butylbromide, the active ingredient ofBuscopan®.In 1951, the new medication was ready for commercial production. Buscopan® waslaunched in 1952. Today, with more than half a century of proven expertise in safeantispasmodic effectiveness, Buscopan® is the world's leading and most trustedtreatment for abdominal pain.

12.4 … and in association with Paracetamol12.4 … and in association with Paracetamol


OH

NH

CH3

O

N

O

O

CH2OHHO

CH3

Br -

+



Buscopan® Plus (also known as Buscapina® Compositum N in somecountries) has a dual effect. Paracetamol, a proven analgesic, reduces the painof uterine cramps. At the same time, Butylscopolamine relieves the painfulcramps of the colon and intestine that often accompany menstrual pain. In thisway, Buscopan® Plus quickly and effectively relieves the pain of menstrualcramps, without interfering in the body's natural menstrual rhythm.

O

12.4 … and an interesting analog.12.4 … and an interesting analog.


N

O

H

CH3

O

CH3

S

S

Br -

+



Tiotropium bromideO

OH

Tiotropium bromide is a muscarinic receptor antagonist, often referred to as anantimuscarinic agent. Although it does not display selectivity for specific muscarinicreceptors, when topically applied it acts mainly on M3 muscarinic receptors located onsmooth muscle cells and submucosal glands. This leads to a reduction in smoothmuscle contraction and mucus secretion and thus produces a bronchodilatory effect.Tiotropium bromide is a long-acting, 24 hour, bronchodilator used in the managementof chronic obstructive pulmonary disease (COPD).

DoDo youyou rememberremember bioisosterebioisostere concept?concept?



N

O

O

CH2OHH

CH3

O

N

O

O

CH2OHH

CH3

O

S

here is an example:

NCH3

12.5 Simplified Analogues12.5 Simplified Analogues

Pharmacophore = Pharmacophore = esterester+ + basic aminebasic amine+ + aromatic ringaromatic ring


NH5C2 CH3CH3

C2H5



O

O

CH2OHH

Amprotropine[3-(diethylamino)-2,2-dimethylpropyl] 3-

hydroxy-2-phenylpropanoate

O

O

CH2OHH

CH3CH3

II needneed youryour guessguess:: moremore oror lessless activeactive thanthan……

N

O

CH2OH

CH3

H

N

O

CH2OH

H5C2

H

CH3CH3

C2H5



O

O

Amprotropine(logP = 3.0)

O

O

Amprotropine is ≈1/100 less active as muscarinic antagonistcompare to atropine, why?

BRAVI!!!



N

O

O

CH2OH

CH3

H

O

O

O

NMe

+

Br -



Propantheline bromideN-isopropyl-N-methyl-N-{2-[(9H-xanthen-9-

ylcarbonyl)oxy]ethyl}propan-2-aminium bromide

Used for the treatment of excessive sweating (hyperhidrosis), cramps or spasms of the stomach, intestines (gut) or bladder, and involuntary urination (enuresis).

O O


Tropicamide (logP = 1.3)(opthalmics)

Cyclopentolate (logP = 2.4)(opthalmics)

Benztropine (logP = 4.3)(Parkinsons disease)

CH

CH2OH

O

N

CH2CH3

N


CH

O

O

OH

Me2N

N

O

CH3

H



(opthalmics) (opthalmics) (Parkinsons disease)

Benzhexol (logP =4.5)(Parkinsons disease)

Pirenzepine (logP = …)(anti-ulcer)

N N

CHN

C O

CH2

N

N

O

Me

N

OH

GiveGive meme anotheranother goodgood idea!idea!

N

O

O

CH2OH

CH3

H

H+



without SNC side effects!!!


Pirenzepine(anti-ulcer)


11-[(4-methylpiperazin-1-yl)acetyl]-5,11-

•• ItIt isis aa MM11 muscarinicmuscarinic antagonistantagonist•• MedicalMedical useuse -- treatmenttreatment ofof motionmotion sicknesssickness

((kinetosiskinetosis),), nausea,nausea, intestinalintestinal crampingcramping• It has no effects on the brain and spinal cord as

it cannot diffuse through the blood-brain barrier

N

NH

N

O

ON



11-[(4-methylpiperazin-1-yl)acetyl]-5,11-dihydro-6H-pyrido[2,3-

b][1,4]benzodiazepin-6-one

logP = 1.53 logP = - 0.61

N

O

O

CH2OH

CH3

H

N

CH3

N

NCH3

N

O

NH

N

O


CH2 instead OpKa (1) ≅ 8

pKa (2) ≅ 5



pKa (3) ≅ 3


Please… don’t forget:Please… don’t forget:



SynthesisSynthesis PathPath





N

NCH3

N

O

NH

O

N

NCH3

N

O

NH

O



Pirenzepine(anti-ulcer, M1 selective)

Telenzepine(anti-ulcer, M1 selective)

logP = -0.61 logP = 0.37

Telenzepine is 25 folds more active than pirenzepine.

ON O

SMe

12.6 Determinants of Gastric Acid Secretion12.6 Determinants of Gastric Acid Secretion




DoDo youyou rememberremember:: atropisomers?atropisomers?Atropisomers are stereoisomers resulting fromhindered rotation about single bonds where thesteric strain barrier to rotation is high enoughto allow for the isolation of the conformers.The word atropisomer is derived from theGreek a, meaning not, and tropos, meaningturn. The name was coined by Kuhn in 1933,but atropisomerism was first detected in 6,6’-dinitro-2,2’-diphenic acid by Cristie in 1922.

Telenzepineis atropisomeric, with a stereogenicC-N axis, and at 20 °C in neutral aqueous



Telenzepineis atropisomeric, with a stereogenicC-N axis, and at 20 °C in neutral aqueoussolution it displays a half-life for racemization of the order of 1000 years. Partial separationof the enantiomers 1 a and 1 b was achieved by exploiting their difference in affinity formuscarinic receptors. The (−)-isomer turned out to be inactive andhas a have much lowerselectivity than the (+)-isomer; a 500-fold difference in activitybetween the atropisomerswas seen at muscarinic receptors in rat cerebral cortex.

12.7 SAR for Antagonists12.7 SAR for Antagonists

R2NCH2

CH2

O

C

O

CH

R'

R'R' = Aromatic or

Heteroaromatic




Important featuresImportant features•• Tertiary amine (ionised) or a quaternary nitrogenTertiary amine (ionised) or a quaternary nitrogen•• Aromatic ringAromatic ring•• EsterEster•• NN--Alkyl groups (R) can be larger than methyl (unlike agonists)Alkyl groups (R) can be larger than methyl (unlike agonists)•• Large branched acyl groupLarge branched acyl group•• R’ = aromatic or heteroaromatic ringR’ = aromatic or heteroaromatic ring•• Branching of aromatic/heteroaromatic rings is importantBranching of aromatic/heteroaromatic rings is important

N

O

O

OHMe

Extra

TM5

TM6TM7

TM1

+

Tyr530Tyr507

+

12.8 Muscarinic binding site12.8 Muscarinic binding site




H

Intra

TM3

Asp148 TM4TM2

Muscarinic M3

12. Cholinergic receptors 12. Cholinergic receptors

Receptor typesReceptor types•• Not all cholinergic receptors are identicalNot all cholinergic receptors are identical•• Two types of cholinergic receptor Two types of cholinergic receptor --nicotinicnicotinic and and muscarinicmuscarinic•• Named after natural products showing receptor selectivityNamed after natural products showing receptor selectivity



Ligand-gated ion channels(ionotropic receptors)

G protein-coupled receptors(metabotropic receptors)

13. Cholinergic Antagonists (Nicotinic receptor)13. Cholinergic Antagonists (Nicotinic receptor)

PharmacophorePharmacophore•• Two quaternary centres at specific separation (≈ 11Two quaternary centres at specific separation (≈ 11ÅÅ))•• Different mechanism of action from atropine based antagonistsDifferent mechanism of action from atropine based antagonists•• Different binding interactionsDifferent binding interactions

γ



≅ 11Å


13.1 Curare13.1 Curare•• Extract from Extract from curaricurari plantplant•• Used for poison arrowsUsed for poison arrows•• Causes paralysis (blocks acetylcholine signals to muscles)Causes paralysis (blocks acetylcholine signals to muscles)•• Active principle = tubocurarineActive principle = tubocurarine

N

MeO

Me



DD--Tubocurarine (DTc)Tubocurarine (DTc)

NHO

O

CH2

OMe

N

Me

Me

H

O

MeCH2

OH

H

H

chondrodendron tomentosum


NHO

MeO

O

Me

MeCH2H

1,2,3,4-tetrahydro-1-benzyl-isoquinoline

Isoquinoline derivativesIsoquinoline derivatives




CH2

OMe

N

Me

H

O

OH

H

10.8 Å

Tubocurarine chloride is a competitive antagonist of nicotinicneuromuscular acetylcholine receptors, used to paralyse patientsundergoing anaesthesia. It is one of the chemicals that can be obtainedfrom curare, itself an extract of Chondodendron tomentosum, a plant foundin South American jungles which is used as a source of arrow poison. Nativeindians hunting animals with this poison were able to eat the animal'scontaminated flesh without being affected by the toxin becausetubocurarine cannot easily cross mucous membranes and is thus inactiveorally.

The correct chemical structure was only elucidated circa 1970, even thoughthe plant had been known since the Spanish Conquest.



the plant had been known since the Spanish Conquest.

The word curare comes from the South American Indian name for the arrowpoison: "ourare". Presumably the initial syllable was pronounced with aheavy glottal stroke. Tubocurarine is so called because the plant samplescontaining it were first shipped to Europe in tubes.

Today, tubocurarine has fallen into disuse in western medicine, as safersynthetic alternatives such as atracurium are available. However,tubocurarine is still used in the United States and elsewhere as part of thelethal injection procedure.


Clinical usesClinical uses•• Neuromuscular blocker for surgical operationsNeuromuscular blocker for surgical operations•• Permits lower and safer levels of general anaestheticPermits lower and safer levels of general anaesthetic•• TubocurarineTubocurarine usedused asas neuromuscularneuromuscular blockerblocker butbut sideside effectseffects

inin particularparticular hypotensionhypotension andand bronchoconstrictionbronchoconstriction (by(byhistaminehistaminereleasereleasefromfrom mastmast cells)cells)



histaminehistaminereleasereleasefromfrom mastmast cells)cells)•• Currently,Currently, tubocurarinetubocurarine isis rarelyrarely usedused asas anan adjunctadjunct forfor

clinicalclinical anesthesiaanesthesia becausebecause safersafer alternativesalternatives

Time to onset: 300 seconds or more

Duration: 60 -120 minutes

(which is relatively slow among neuromuscular-blocking drugs)

(which is relatively long time)

Short duration

CommonCommon classificationclassification……



Intermediate duration

Long duration

NotNot onlyonly DD--TubocurarineTubocurarine……



Toxiferine d (N+-N+) ≅ 9.9 Å Strychnos toxifera



C-Curarine d (N+-N+) ≅ 9.5 Å Lagenaria siceraria

Calebassine d (N+-N+) ≅ 10.2 Å Strychnos usambarensis



Duration of paralysis (paralytic dose i.v.), contraction of catgastrocnemius by electrically stimulated sciatic nerve ( 4x/min). [J.E. Saxton “The Alkaloids” Vol. 1, p.330, 1970]


From DFrom D--Tubocurarine to MetocurineTubocurarine to Metocurine

NHO

MeO

O

CH2

N

Me

Me

H

O

MeCH2

H

H

NHO

MeO

O

CH2

Me

MeO

MeCH2

H

H

Me

Me




OMe

NH OH

Metocurine is a semisynthetic derivative of DTc, first synthesized by King in 1935 as part of thework that first suggested a chemical structure for DTc. It is the N,O,O-trimethylated compound.Unlike DTc, it is a bisquaternary molecule. Metocurine is about twice as potent as curare inhuman subjects , with a similarly long duration of action. Its principal advantage over curare is itsweaker histamine-releasing property-less than one-half that of DTc. Metocurine is indicated forlonger operations (3–4 hours). Metocurine is excreted only by the kidney. It has no alternate biliarypathway, and no metabolism occurs in the liver.

OMe

NH OHMe

MetocurineMetocurine

Me

13.3 Analogues of tubocurarine (simplification strategy) 13.3 Analogues of tubocurarine (simplification strategy)


Neuromuscular blocking drugs are often classified into two broadclasses:

Pachycurares, which are bulky molecules with non-depolarizingactivity ;



activity ;

Leptocurares, which are thin and flexible molecules that tend tohave depolarizing activity.

13.3 Analogues of tubocurarine (simplification strategy) 13.3 Analogues of tubocurarine (simplification strategy)


NHO

MeO

O

Me

MeCH2H



CH2

OMe

N

Me

H

O

OH

H


PharmacophorePharmacophore•• Changing of the Ach:NicRec stoichiometry 2:1 to 1:1Changing of the Ach:NicRec stoichiometry 2:1 to 1:1

γ



≅11Å

13.3 Analogues of tubocurarine13.3 Analogues of tubocurarine

DecamethoniumDecamethonium

Me3N(CH2)10NMe3




•• Long lastingLong lasting•• Long recovery timesLong recovery times•• Side effects on heartSide effects on heart

((VOC blockerVOC blocker))



ON

CH3

CH3

CH3CH3

O+

ON

CH3

CH3

CH3CH3

O+



Suxamethonium Suxamethonium or succinylcholineor succinylcholine

Me3NCH2CH2 OC

O

CH2

C

O

O CH2CH2NMe3CH2

≅ 5 Å

gauche


Suxamethonium Suxamethonium or succinylcholineor succinylcholine

Me3NCH2CH2 OC

O

CH2

C

O

O CH2CH2NMe3CH2


Suxamethonium chloride (otherwise known as succinyl chloride or “sux”) is a drug used to



The discovery and development of suxamethonium led to a Nobel Prize inmedicine for Daniel Bovet in 1957.

create short-term muscle paralysis. The drug can effectively stop the action of all skeletalmuscles in the body in30-60 secondsenabling doctors to perform a Tracheal Intubation(placing a flexible plastic tube into the trachea to maintain an openairway as shown in thediagram) without the patient struggling. The effect typically lasts 5-10 minutesmeaningthat the patient does not need to have artificial breathing for too long.

O O



NHO

MeO

O

Me

MeCH2H



SuxamethoniumSuxamethonium

Me3NCH2CH2 OC

CH2

CO CH2CH2NMe3CH2

DD--TubocurarineTubocurarine

CH2

OMe

N

Me

H

O

OH

H


AtracuriumAtracurium

NCH2 CH2

C

O

O

MeO

HN

(CH2)5MeO OC

OMe

O

CH2 CH2

Me

MeO

OMe

OMe


Me

* *



•• Stereochemical problem: also ammonium salts become chirals!Stereochemical problem: also ammonium salts become chirals!•• Atracurium has been utilized as a mix of all stereoisomers!Atracurium has been utilized as a mix of all stereoisomers!

AtracuriumAtracuriumOMe

OMe MeO

OMe



NCH2 CH2

C

O

O

MeO

HN

(CH2)5MeO OC

OMe

O

CH2 CH2

Me

MeO

OMe

OMe


Me



•• Design based on tubocurarine and suxamethoniumDesign based on tubocurarine and suxamethonium•• Lacks cardiac side effectsLacks cardiac side effects•• Rapidly broken down in blood both chemically and metabolicallyRapidly broken down in blood both chemically and metabolically•• Avoids patient variation in metabolic enzymesAvoids patient variation in metabolic enzymes•• Administered as an i.v. dripAdministered as an i.v. drip•• Self destruct system limits lifetimeSelf destruct system limits lifetime


OMe MeO

OMe

Time to onset: 90 or more (seconds)Duration: 30 or less (minutes)


NMe

CH2

Ph

CH C

H O

R -HCHH2C C

OPh

RN

Me




AtracuriumAtracurium stablestable atat acidacid pHpHHofmannHofmann eliminationelimination atat bloodblood pHpH ((77..44)):: HofmannHofmann eliminationelimination providedprovided preciselypreciselythisthis basisbasis:: itit isis aa chemicalchemical processprocess inin whichwhich aa suitablysuitably activatedactivated quaternaryquaternaryammoniumammonium compoundcompound cancan bebe degradeddegraded byby thethe mildlymildly alkalinealkaline conditionsconditions presentpresentatat physiologicalphysiological pHpH andand temperaturetemperature.. InIn effect,effect, HofmannHofmann eliminationelimination isis aa retroretro--MichaelMichael additionaddition chemicalchemical processprocess..

Ph

ACTIVE

PhINACTIVE



NCH2 CH2

C

O

O

MeO

HN

(CH2)5MeO OC

OMe

O

CH2 CH2

Me

MeO

OMe

OMe


Me

Cisatracurium




OMe MeO

OMeCisatracurium

5-[3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoyloxy]pentyl 3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propanoate

Time to onset: 90 (seconds)Duration: 60 - 80 (minutes)

SynthesisSynthesis PathPath

1,2,3,4-tetrahydropapaverine





Pancuronium (R=Me)Pancuronium (R=Me)

Vecuronium (R=H)Vecuronium (R=H)

MeO

NMeN Me

Me

O

H H

HR



•• Steroid acts as a spacer for the quaternary centres (≈ 11Steroid acts as a spacer for the quaternary centres (≈ 11ÅÅ))•• Acyl groups are added to introduce the Ach skeletonAcyl groups are added to introduce the Ach skeleton•• Faster onset then tubocurarine but slower than suxamethoniumFaster onset then tubocurarine but slower than suxamethonium•• Longer duration of action than suxamethonium (> 45 min)Longer duration of action than suxamethonium (> 45 min)•• No effect on blood pressure and fewer side effectsNo effect on blood pressure and fewer side effects

O

MeO

H

DoDo youyou remember?remember?Decalin

(decahydronaphthalene)

H2

Naphthalene



trans cis

Naphthalene



10.6 ÅTime to onset: 240 (seconds)Duration: 120 - 180 (minutes)



Pancuronium (R=Me)Pancuronium (R=Me)Me

O

NMeN

O

Me

Me

Me

O

O

H

H H

HR



Pancuronium (R=Me)Pancuronium (R=Me)Me

O

NMeN

O

Me

Me

O

H H

HR



O

MeO

H

It is also used as one component of alethal injection (typically a barbiturate, pancuronium,and potassium solution) in administration of thedeath penalty in some parts of the UnitedStates.





Rocuronium bromide

Time to onset: 75 (seconds)Duration: 45 - 70 (minutes)

In addition, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors, as allosteric modulators.

Adverse effects:

extra



Family A

intra

ORTHOSTERIC SITE ALLOSTERIC SITE

“CHIMICA FARMACEUTICA ETOSSICOLOGICA II”



Stefano Moro

Chimica e Tecnologia Farmaceutiche

13.3 Botulinic toxin13.3 Botulinic toxin

Botox ® (in Italy sells as Vistabex®)Botox ® (in Italy sells as Vistabex®)•• ResearchersResearchers discovereddiscovered inin thethe 19501950ss thatthat

injectinginjecting overactiveoveractive musclesmuscles withwith minuteminutequantitiesquantities ofof botulinumbotulinum toxintoxin typetype--AA wouldwouldresultresult inin decreaseddecreased musclemuscle activityactivity bybyblockingblocking thethe releaserelease ofof acetylcholineacetylcholine fromfrom




blockingblocking thethe releaserelease ofof acetylcholineacetylcholine fromfromthethe neuronneuron byby preventingpreventing thethe vesiclevesicle wherewherethethe AcetylcholineAcetylcholine isis storedstored fromfrom bindingbinding totothethe membranemembrane wherewhere thethe neurotransmitterneurotransmittercancan bebe releasedreleased.. ThisThis willwill renderrender thethe musclemuscleunableunable toto contractcontract forfor upup toto aa periodperiod ofofthreethree toto fourfour monthsmonths..

13.3 Botulinic toxin13.3 Botulinic toxin




colinergici, anticolinergici &...

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