Buscopan®) H O CH2OH O

Home , Cyclopentolate, Muscarinic toxin 7, Propantheline bromide, Tropicamide

COLINERGICI, ANTICOLINERGICI & ANTICOLINESTERASICI

Parte II

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 12. Cholinergic receptors Receptor types •• Not all cholinergic receptors are identical •• Two types of cholinergic receptor -- nicotinic and muscarinic •• Named after natural products showing receptor selectivity

Ligand-gated ion channels G protein-coupled receptors (ionotropic receptors) (metabotropic receptors)

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

Postsynaptic Postsynaptic nerve nerve

Ach Ach Ach

Antagonist

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

Uses •• Shutting down digestion for surgery •• Ophthalmic examinations •• Relief of peptic ulcers •• Treatment of Parkinson’s Disease •• Anticholinesterase poisoning •• Motion sickness

Ethylene bridge

NMe3 Me O

Acetoxy 44 oo Nitrogen From agonist to antagonist: O O O

H3C O

Agonist Antagonist (mainly muscarinic)

12.1 Atropine α-tropanol

N H3C

H Atropa Belladonna (Solanaceae ) CH2OH O

Tropic acid

1 2 8

5 4 3 7 6 8-methyl-8-azabicyclo[3.2.1]octane

Atropine Cocaine

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

Mother nature…

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

THF H2O (H 2SO 4, pH = 3.4)

95 : 5 25 : 75

versus the human chemistry!

12.1 Atropine… or D/L Hyscymine N H3C easily racemised H CH2OH O * O

12.1 Atropine L = 15.6 Å Vol ≅ 290 Å3

eq log P = 1.8 MW = 289.4 PSA ≅ 50 Å2 O + N = 4 ax pKa = 9.4

Ep (eq) = 47.9 kcal/mol

Ep (ax) = 49.6 kcal/mol

N 12.1 Atropine H3C

H CH2OH O

O •• Racemic form of hyoscyamine ((RR form) •• Source -- roots of belladonna (1831) ( Atropa Belladonna )) •• Used as a poison •• Used as a medicine decreases GIT motility antidote for anticholinesterase poisoning resuscitation dilation of eye pupils •• CNS side effects --hallucinationshallucinations Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 12. Cholinergic Antagonists (Muscarinic receptor)

12.1 Atropine N H3C

H CH2OH O

A common mnemonic used to describe the physiologic manifestations of Atropine overdose is: hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter !

These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased sweating/lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome , and may also be caused by other drugs with anticholinergic effects, such as scopolamine, diphenhydramine, phenothiazine antipsychotics and benztropine.

12.1 Atropine N H3C

H CH2OH O

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

12.1 Atropine

N H3C

H CH2OH O

12.3 Comparison of atropine with acetylcholine

NNMe3 H3C

CH2 CH2 H CH2OH OO CH3 anti conformation is fixed! C OO •• Relative positions of ester and nitrogen similar in both molecules •• Nitrogen in atropine is ionised •• Amine and ester are important binding groups (ionic + H--bonds)bonds) •• Aromatic ring of atropine is an extra binding group (vdW) •• Atropine binds with a different induced fit --nono activationactivation •• Atropine binds more strongly than acetylcholine

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Pharmacodynamics versus Pharmacokinetics: H + N N H3C H3C - H+ H CH OH H 2 logP=1.8 CH2OH + + H O O O O

12.2 Hyoscine (scopolamine)

Me N

H O CH2OH Scopolia Japonica (Solanaceae) H O CH C * H epoxide O

12.2 Hyoscine (scopolamine) Me N

H O CH2OH H O CH C * H O

•• It is mostly a M1 muscarinic antagonist •• Treatment of nausea and motion sickness ( transdermal route ).). •• To reduce motility and secretions in the GI tract . •• Treatment of intestinal cramping. •• AsAs ananadjunctadjunct totoopioid analgesia, such asasthethe product Twilight Sleep which contained morphine and scopolamine.. scopolamine This combination induces aasemisemi--narcoticnarcotic state which produces thethe experience ofofchildbirthchildbirthwithout pain, ororwithoutwithout thethe memory ofofpainpain.. It is now merely a chapter in the past history of obstetrics.

12.2 Hyoscine (scopolamine)

pKa = 9.7 pKa = 7.7

MCHe 3 H C N 3 N

H CH OH H 2 O CH2OH O H O CH C * O H O

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Smooth muscle signal trasduction: M muscarinic receptor 1 beta 2 adrenergic receptor H1 histamine receptor Oxytocin receptor H2 histamine receptor P2Y purinerig receptor Endothelin receptors DAG PLCPLC PKC Adenylate Cyclase ATP GGss GGqq stimulate stimulate cAMP IP 3 PKA CaCa 2+2+ P CaCa 2+2+ CaCa 2+2+ CaCa 2+2+ P ER CaCa +2+2 /calmodulin + - MLCK myosin light chain kinase actin P P CONTRACTION myosin myosin RELAXATION

MLCP

Confidential and Property of ©2012 Molecular Modeling Section myosin light chain phosphatase M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy IP 3 PKA CaCa 2+2+ P CaCa 2+2+ CaCa 2+2+ CaCa 2+2+ P ER CaCa +2+2 /calmodulin + - MLCK myosin light chain kinase actin P P CONTRACTION myosin myosin RELAXATION

cGMP-dependent MLCP protein kinase myosin light chain phosphatase

cGMP 5’-GMP GTP - soluble guanylyl cyclase PDEPDE--55 Sildenafil

locally Confidentialproduced and Property NO of ©2012 Molecular Modeling Section (Viagra®) M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Sildenafil (Viagra®) log P = 1.9 MW = 474.5 2 PSA ≅ 110 Å PDB code: 1UDT O + N = 10 pKa = 8.7 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 corpus cavernosum, leading to smooth muscle relaxation (vasodilatation) of the intimal cushions of the helicine arteries . This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Other drugs that operate by the same mechanism include Tadalafil (Cialis) and Vardenafil (Levitra). Sildenafil is metabolized by liver enzymes and excreted by both the liver and kidneys. Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy To cross … or not to cross, this is the dilemma! H N + H3C

H CH2OH O

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy To cross … or not to cross, this is the dilemma! H N + H3C

H CH2OH O

without peripheral and SNC side effects!!!

12.4 The first good idea: the analogues of atropine

- NO 3 CH3 H C N 3 N + H3C

H CH OH 2 H CH2OH O O O O

Atropine methonitrate •• Analogues are fully ionised •• Analogues unable to cross membranes including BBB •• No CNS side effects

CH3 Br CH(CH3)2 NO3 H3C N H3C N

H H CH2OH CH2OH O CH O CH C C O O

Atropine methonitrate Ipratropium

Inhalation administration: Oral administration: 1. treat and prevent minor and 1. treat pain and discomfort moderate bronchial asthma; caused by abdominal 2. treat of chronic obstructive cramps, or other pulmonary disease (COPD). spasmodic activity in the 3. It is also combined with digestive system. Salbutamol (beta 2 adrenergic agonist) for the management of COPD and asthma.

12.4 The most famous quaternary nitrogen analogue! Br -

H3C + N Butylscopolamine (Buscopan®) H O CH2OH O

O •• Butylscopolamine isis used toto treat pain and discomfort caused byby abdominal cramps, menstrual cramps, oror other spasmodic activity inin the digestive system.. ItIt isis not anananalgesicanalgesic inin the normal sense, since itit doesn't 'mask' oror'cover'cover over' the pain, but rather works toto prevent painful cramps and spasms from occurring ininthe first placeplace..

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 oldest cultures. Ancient Hindu physicians in India knew of the antispasmodic effects of a relative of Duboisia : the plant Datura . Today, the Buscopan® story starts in Ingelheim, Germany, where elite Duboisia plants are grown in greenhouses. These plants are bred to be resistant against nematodes and beetles . The best seeds are harvested and then delivered to the company´s plantations in South America and Australia for further on-site selection. Here, the shrubs grow on a large scale. The pharmaceutically important alkaloid scopolamine which is contained in the dried leaves and stalks is isolated and purified. Finally, the active precursor substance scopolamine is converted in a single chemical process into hyoscine butylbromide, the active ingredient of Buscopan®. In 1951, the new medication was ready for commercial production. Buscopan® was launched in 1952. Today, with more than half a century of proven expertise in safe antispasmodic effectiveness, Buscopan® is the world's leading and most trusted treatment for abdominal pain.

12.4 … and in association with Paracetamol

Br -

H3C + N H N CH3

O H CH OH O 2 HO O

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

12.4 … and an interesting analog. Br -

CH3 H3C + N

S H O S O

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

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Do you remember bioisostere concept?

here is an example:

CH3 CH3 N N

H O CH2OH H O CH2OH O O S

O O

12.5 Simplified Analogues

Pharmacophore = ester + basic amine + aromatic ring

C2H5 H C N 3 H C N 5 2 H C 3 CH3 H CH2OH H CH2OH O O

O O Amprotropine [3-(diethylamino)-2,2-dimethylpropyl] 3- hydroxy-2-phenylpropanoate

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy I need your guess : more or less active than…

C2H5 H C N H C N 3 5 2 H C 3 CH3 H H CH2OH CH2OH O O

O O Amprotropine (logP = 3.0) Amprotropine is ≈1/100 less active as muscarinic antagonist compare to atropine, why? BRAVI!!! Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 12. Cholinergic Antagonists (Muscarinic receptor)

12.5 Simplified Analogues

- Br N H3C

N + H CH OH Me 2 O O O

O O

Propantheline bromide N-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). Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 12. Cholinergic Antagonists (Muscarinic receptor)

12.5 Simplified Analogues N H3C Me N N 2 O H CH O CH2CH3 N O OH CH O

CH2OH Tropicamide (logP = 1.3) Cyclopentolate (logP = 2.4) Benztropine (logP = 4.3) (opthalmics) (opthalmics) (Parkinsons disease) O

HN C

N N N C O

CH2

HO N Benzhexol (logP =4.5) Pirenzepine (logP = …) (Parkinsons disease) N (anti-ulcer) Me Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Give me another good idea! H N + H3C

H CH2OH O

without SNC side effects!!!

O H N •• ItIt isis aaMM11muscarinicmuscarinicantagonist •• Medical use --treatment ofofmotion sickness N N ((kinetosiskinetosis),), nausea, intestinal cramping Pirenzepine O • It has no effects on the brain and spinal cord as N (anti-ulcer) it cannot diffuse through the blood-brain barrier 11 -[(4 -methylpiperazin -1-yl)acetyl] -5,11 - N dihydro-6H-pyrido[2,3- b][1,4]benzodiazepin-6-one H3C

H C N 3 H C N 3 O H CH2OH N N NH O O N O logP = 1.53 logP = - 0.61

pKa (2) ≅ 5

pKa (1) ≅ 8 CH2 instead O

pKa (3) ≅ 3

Please… don’t forget:

N N H3C H C O 3 O

N N NH N N NH O N O Me S

Pirenzepine Telenzepine (anti-ulcer, M1 selective) (anti-ulcer, M1 selective) logP = -0.61 logP = 0.37

Telenzepine is 25 folds more active than pirenzepine. Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 12. Cholinergic Antagonists (Muscarinic receptor) 12.6 Determinants of Gastric Acid Secretion

Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The word atropisomer is derived from the Greek a, meaning not , and tropos, meaning turn . 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.

Telenzepine is atropisomeric, with a stereogenic C-N axis, and at 20 °C in neutral aqueous solution it displays a half-life for racemization of the order of 1000 years. Partial separation of the enantiomers 1 a and 1 b was achieved by exploiting their difference in affinity for muscarinic receptors. The (−)-isomer turned out to be inactive and has a have much lower selectivity than the (+)-isomer; a 500-fold difference in activity between the atropisomers was seen at muscarinic receptors in rat cerebral cortex.

R' R' = Aromatic or Heteroaromatic CH2 O CH R2N CH2 C R'

O Important features •• Tertiary amine (ionised) or a quaternary nitrogen •• Aromatic ring •• Ester •• N--AlkylAlkyl groups (R) can be larger than methyl (unlike agonists) •• Large branched acyl group •• R’ = aromatic or heteroaromatic ring •• Branching of aromatic/heteroaromatic rings is important

TM6 Extra TM7 Tyr507 TM5 Tyr530 O TM1 O

Me N ++ OH TM2 H Asp148 TM4

TM3

Intra Muscarinic M3

Ligand-gated ion channels G protein-coupled receptors (ionotropic receptors) (metabotropic receptors)

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 13. Cholinergic Antagonists (Nicotinic receptor)

Pharmacophore •• Two quaternary centres at specific separation ( ≈ 1111ÅÅ)) •• Different mechanism of action from atropine based antagonists •• Different binding interactions

≅ 11Å

13.1 Curare •• Extract from curari plant •• Used for poison arrows •• Causes paralysis (blocks acetylcholine signals to muscles) •• Active principle = tubocurarine

MeO

Me N HO Me CH2 O H

CH H 2 Me O H N OH

OMe chondrodendron tomentosum DD--TubocurarineTubocurarine (DTc) Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 13. Cholinergic Antagonists (Nicotinic receptor)

Isoquinoline derivatives MeO

Me N HO Me CH2 O H 1,2,3,4-tetrahydro-1-benzyl-isoquinoline

CH H 2 Me O H N OH

OMe

10.8 Å DD--TubocurarineTubocurarine (DTc)

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy use wever, atients animal's the arrow e obtained us inactive ison. Native ine, as safer as part of the plant samples , a plant found ounced with a S.MORO – CFTII 2016/2017 70, even though . Conquest Spanish g Section g Chondodendron tomentosum the University ofPadova - Italy since known chloride is a competitive antagonist of nicotinic been had Confidential and PropertyConfidentialand of ©2012Molecular Modelin plant Dept. Pharmaceutical Pharmacologicaland Sciences – S undergoing anaesthesia. It is one ofin South the American jungles chemicals whichindians is that used as hunting can a source b animalscontaminated of arrow with po flesh thistubocurarine cannot poison easily without were crossorally. mucous able being membranes to and is eat affected th the The correct by chemical structure was only the elucidated circa 19 toxin beca neuromuscular acetylcholine receptors, used to paralyse p the The word curare comes from the South American Indian name for poison: "ourare". Presumablyheavy the glottal stroke. initial Tubocurarinecontaining syllable is it were so was first shipped called pron to because Europe in the tubes. Today, tubocurarine hassynthetic fallen into alternatives disusetubocurarine is in still western such usedlethal medic in injection the procedure. as United States and atracurium elsewhere are available. Ho Tubocurarine from curare, itself an extract of M M 13. Cholinergic Antagonists (Nicotinic receptor)

Clinical uses •• Neuromuscular blocker for surgical operations •• Permits lower and safer levels of general anaesthetic •• Tubocurarine used asasneuromuscularneuromuscular blocker but side effects inin particular hypotension and bronchoconstriction (by histamine release from mast cells) •• Currently, tubocurarine isis rarely used asasananadjunctadjunct for clinical anesthesia because safer alternatives

Time to onset: 300 seconds or more (which is relatively slow among neuromuscular-blocking drugs) Duration: 60 -120 minutes (which is relatively long time)

Short duration

Intermediate duration

Long duration

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

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Calebassine d (N+-N+) ≅ 10.2 Å Strychnos usambarensis

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

From D--TubocurarineTubocurarine to Metocurine

MeO MeO

Me Me N N HO Me Me HO Me H CH2 CH2 O O H

CH2 CH H H 2 Me Me O O H N OH Me H N OHMe

OMe OMe DD--TubocurarineTubocurarine (DTc) Metocurine

Metocurine is a semisynthetic derivative of DTc, first synthesized by King in 1935 as part of the work 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 in human subjects , with a similarly long duration of action. Its principal advantage over curare is its weaker histamine-releasing property-less than one-half that of DTc. Metocurine is indicated for longer operations (3–4 hours). Metocurine is excreted only by the kidney. It has no alternate biliary pathway, and no metabolism occurs in the liver .

13.3 Analogues of tubocurarine (simplification strategy)

Neuromuscular blocking drugs are often classified into two broad classes:

Pachycurares , which are bulky molecules with non-depolarizing activity ;

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

13.3 Analogues of tubocurarine (simplification strategy)

MeO

Me N HO Me CH2 O H

CH H 2 Me O H N OH

OMe

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

≅11Å

13.3 Analogues of tubocurarine

Me3N(CH2)10NMe3

Decamethonium

•• Long lasting •• Long recovery times •• Side effects on heart ((VOC blocker ))

13.3 Analogues of tubocurarine

CH O O CH 3 + 3 + CH H3C N N 3 O CH H C O 3 3 CH H3C 3

gauche

≅ 5 Å O O

C C Me3NCH2CH2 O CH2 CH2 O CH2CH2NMe3 Suxamethonium or succinylcholine

13.3 Analogues of tubocurarine

O O

C C Me3NCH2CH2 O CH2 CH2 O CH2CH2NMe3 Suxamethonium or succinylcholine Suxamethonium chloride (otherwise known as succinyl chloride or “sux”) is a drug used to create short-term muscle paralysis. The drug can effectively stop the action of all skeletal muscles in the body in 30-60 seconds enabling doctors to perform a Tracheal Intubation (placing a flexible plastic tube into the trachea to maintain an open airway as shown in the diagram) without the patient struggling. The effect typically lasts 5-10 minutes meaning that the patient does not need to have artificial breathing for too long. The discovery and development of suxamethonium led to a Nobel Prize in medicine for Daniel Bovet in 1957.

13.3 Analogues of tubocurarine

MeO

Me N HO Me CH2 O H O O

C C Me NCH CH O CH CH O CH CH NMe CH 3 2 2 2 2 2 2 3 H 2 Me O H N OH Suxamethonium

OMe

DD--TubocurarineTubocurarine

13.3 Analogues of tubocurarine

MeO OMe O O Me MeH N C C N MeO * CH2 CH2 O (CH2)5 O CH2 CH2 * OMe

Atracurium OMe MeO OMe OMe

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

13.3 Analogues of tubocurarine

MeO OMe O O Me MeH N C C N MeO CH2 CH2 O (CH2)5 O CH2 CH2 OMe

Atracurium OMe MeO OMe OMe •• Design based on tubocurarine and suxamethonium •• Lacks cardiac side effects •• Rapidly broken down in blood both chemically and metabolically •• Avoids patient variation in metabolic enzymes •• Administered as an i.v. drip •• Self destruct system limits lifetime Time to onset: 90 or more (seconds) Duration: 30 or less (minutes)

13.3 Analogues of tubocurarine

Me R -H Me R N N CH2 CH C H2CCCH O H O Ph Ph ACTIVE INACTIVE

Atracurium stable atatacidacid pH Hofmann elimination atatblood pHpH ((77..44))::HofmannHofmann elimination provided precisely this basis:: basis itit isis aachemicalchemical process ininwhich aasuitablysuitablyactivated quaternary ammonium compound can bebe degraded byby the mildly alkaline conditions present atatphysiological pHpH and temperature.. temperature InIneffect, Hofmann elimination isis aaretroretro-- Michael addition chemical process.. process Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 13. Cholinergic Antagonists (Nicotinic receptor)

13.3 Analogues of tubocurarine

MeO OMe O O Me MeH N C C N MeO CH2 CH2 O (CH2)5 O CH2 CH2 OMe

CisatracuriumAtracurium OMe MeO OMe OMe

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)

1,2,3,4-tetrahydropapaverine

O Me Me Pancuronium (R=Me) R Vecuronium (R=H) Me H N N Me HH

O H

O Me •• Steroid acts as a spacer for the quaternary centres ( ≈ 11Å11 Å)) •• Acyl groups are added to introduce the Ach skeleton •• Faster onset then tubocurarine but slower than suxamethonium •• Longer duration of action than suxamethonium (> 45 min) •• No effect on blood pressure and fewer side effects Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Do you remember? Decalin (decahydronaphthalene)

Naphthalene

trans cis

13.3 Analogues of tubocurarine

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

O Pancuronium (R=Me) O Me Me R Me H N N Me HH

O H

O Me Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy 13. Cholinergic Antagonists (Nicotinic receptor)

13.3 Analogues of tubocurarine O Pancuronium (R=Me) O Me Me R Me H N N Me HH

O H

O Me

It is also used as one component of a lethal injection (typically a barbiturate, pancuronium, and potassium solution) in administration of the death penalty in some parts of the United States.

13.3 Analogues of tubocurarine

Rocuronium bromide

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

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy Adverse effects: 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.

extra

intra

Family A

ORTHOSTERIC SITE ALLOSTERIC SITE

Confidential and Property of ©2012 Molecular Modeling Section M S.MORO – CFTII 2016/2017 M SDept. Pharmaceutical and Pharmacological Sciences – University of Padova - Italy “CHIMICA FARMACEUTICA E TOSSICOLOGICA II”

Stefano Moro

Chimica e Tecnologia Farmaceutiche

13.3 Botulinic toxin Botox ® (in Italy sells as Vistabex®) •• Researchers discovered ininthe 19501950ssthat injecting overactive muscles with minute quantities ofof botulinum toxin typetype--AA would result inindecreased muscle activity byby blocking the release ofof acetylcholine from the neuron byby preventing the vesicle where the Acetylcholine isis stored from binding toto the membrane where the neurotransmitter can bebe releasedreleased..ThisThiswill render the muscle unable toto contract for upup toto aaperiodperiod ofof three totofour months.. months

13.3 Botulinic toxin