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Sostanze naturali che interagicono prevalentemente con i recettori
Muscarinici (M1-M5) con attività parasimpaticolitica (antagonisti).
OH
O
O
N
3-Hydroxy-2-phenyl-propionic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester
Atropine occurs in the deadly nightshade plant (Atropa belladonna)
along with hyoscyamine. This plant has brown-purple flowers and
berries which change from red to purple as the summer progresses.
Hyoscyamine is optically active, while atropine is (±)-hyoscyamine.
OH
O
O
O
O
N
Scopolamina, (S)Ioscina
3-Hydroxy-2-phenyl-propionic acid 9-methyl-3-oxa-9-aza-tricyclo[3.3.1.02,4]non-7-yl ester
Anticolinergico di tipo muscarinico con attività sia centrale (antiemetico,
coadiuvante nella patologia del parkinson e dell’epilessia) che periferica
(secrezioni esocrine e tratto gastrointestinale).
Analoghi atropinici/scopolaminici di sintesi che interagicono prevalentemente
con i recettori muscarinici (M1-M5) con attività parasimpaticolitica.
O
Scopolamina
+
Br-
+
Br O
Ipratropio bromuro
8-isopropil-noratropina-metil bromuro
Buscopan
3-Hydroxy-2-phenyl-propionic acid 9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester 9-butyl bromuro
Analoghi scopolaminici di sintesi che interagicono prevalentemente
con i recettori muscarinici (M1-M5) con attività parasimpaticolitica.
O
Scopolamina
+
Tiotropium bromide is a long-acting, 24 hour, anticholinergic
bronchodilator used in the management of chronic obstructive
pulmonary disease (COPD).
Adverse effects are mainly related to its antimuscarinic effects.
Common adverse drug reactions (≥1% of patients) associated
with tiotropium therapy include: dry mouth and/or throat irritation.
Br O
Buscopan
3-Hydroxy-2-phenyl-propionic acid 9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl ester 9-butyl bromuro
Analoghi atropinici di sintesi che interagicono prevalentemente con i recettori
muscarinici (M1-M5) con attività parasimpaticolitica.
N
Esempio di modifiche del residuo acido
O
O
OH
Omatropina
Hydroxy-phenyl-acetic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester
Esempio di modifiche del residuo acido e della base
+
N Br-
O
O
OH
Trospium bromide
Derivati di sintesi che interagicono prevalentemente con i recettori muscarinici
(M1-M5) con attività parasimpaticolitica.
N
gruppo aminico
SPACER
O
funzione esterea o isosteri
O
R
O
HO
O
O
N
O
N + Br-
Mepenzolato
3-(idrossi-difenil-acetil)-ossi-1,1-dimetil piperidinio bromuro
Adifenina
Diphenyl-acetic acid 2-diethylamino-ethyl ester
Derivati di sintesi che interagicono prevalentemente con i
recettori muscarinici (M1-M5) con attività parasimpaticolitica.
O
O
O
N
+
Br-
Propantelina
N-2-(9H-xanten-9-il-carbonil-ossi)-etil-N-metil-N,N-diisopropil-ammina bromuro
Antagonists of the cholinergic (muscarinic) receptors
for the Prakinson desease
N
Benzatropina
O
3-Benzhydryloxy-8-methyl-8-aza-bicyclo[3.2.1]octane
Esempio di un antistaminico con attività centrale di tipo colinergico come
palliativo nella terapia di parkinson
O
N
Orfenadrina
Dimethyl-[2-(phenyl-o-tolyl-methoxy)-ethyl]-amine
Sostanze di sintesi che interagicono selettivamente con i recettori
Muscarinici (M1-M5) con attività parasimpaticolitica.
Profilo di selettività della pirenzepina
M1>M4>M3>M2
O
HN
N
gruppo aminico
N
N
SPACER
O
O
N
funzione esterea o isosteri
O
R
N
Pirenzepina
11-[(4-Methyl-piperazin-1-yl)-acetyl]-5,11-dihydro-6H-pirido[2,3-b][1,4]-benzodiazepin-6-one
Ach
Parasympathetic
pathway, vagus nervous
Pirenzepina
m1
m3
Ach
stomach
histamine
mastcell
Ach
m1
m1
M1 receptors are located in the myenteric
plexus and the paracrine cells of the mucosa,
whereas M3 are found in the parietal cells.
Design of selective muscarinic receptor ligands
Cholinergic modulation on the broncus and on the hear
Parasympathetic
pathway, vagus
Ach
Ach
m1
m2
-
m3
Airway smooth muscle
Cholinergic modulation on the broncus and on the heart
Ipratropium nonselective compound, m1,2,3
+
sympathetic pathway
-
m2
NA
b
Ach
Parasympathetic
pathway, vagus
m1
-
m2
Mechanism of bradycardic activity
ipratropium
Activity of M2 antagonists in the CNS
Muscarinic autoreceptors (M2) located presynaptically on cholinergic nerve
terminals, are associated with the inhibitory feedback regulation of ACh release.
Muscarinic M2 receptor antagonists such as himbacine and AF-DX116 have been
demonstrated to increase the levels of ACh release in rat striatum.
Since increased levels of ACh are beneficial for the improvement of cognition,
we have embarked on the discovery of potent and selective muscarinic M2 receptor
antagonists for the treatment of neurodegenerative diseases such as Alzheimer's
disease (AD).
Glutamate release
Presynaptic fibres
Ach
M2
N
M1
M2
M3
Postsynaptic fibres
Improvement of cognitive performance
Implication of cholinergic receptors in blood pressure
regulation
Major signal transduction mechanisms found in cells of the cardiovascular system
R, receptor; Gs and Gi, stimulatory and inhibitory G-proteins; AC, adenylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate;
IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; PK, protein kinase; SR, sarcoplasmic reticulum; a and b , adrenoceptor
agonist; M2, muscarinic receptor agonist; A1, adenosine receptor agonist; AII, angiotensin receptor agonist; ET-1, endothelin.
b-adrenergic agonists (b3 in particular) induce relaxation of the bladder body
a-adrenergic agonists (a1a in particular) increase urethral tone and closure pressure
Anthicholinergic agents (muscarinic) decrease the response to cholinergic stimulation
The phatology of the overactive bladder
the role of adrenergic system
Differential expression of a1 subtypes in various tissues is well-documented, and
while the role of each a1 receptor subtype in urethral smooth muscle tone and
contraction is not fully understood, data suggest that a1a selective agonists have an
increased likelihood of achieving an acceptable therapeutic index.
b-Adrenergic agonists
Isoproterenol, Terbutaline
a-Adrenergic agonists
Ephedrine, Pseudoephedrine, Phenypropanolamine
The interest in identifying selective a1a agonists was derived from the limited success
of a adrenergic agonists, pseudoephedrine in treating stress urinary incontinence and
the hypothesis that undesired cardiovascular effects seen with these compounds might
be diminished in compounds with high functional selectivity for the a1a receptor.
The predominant receptors involved in voiding human bladder
Human bladder contains a mixed population of m2 and m3 receptors and
incontinence, due to baldder hypercontractility, is mediated through an
increased stimulation of m3 receptor, the role of m2 receptor is of minor
importance.
By the way, in pathology of asthma the role of m2 muscarinic autoreceptor is
loss and this causes an increse of Ach release and a hyperreactivity
mediated by the stimulation of m3 receptor constitutively present on the
muscle airways.
Parasympathetic
pathway, vagus
m1
sympathetic pathway
m2
-
Also, it is well known the role of m2 receptor
in the control of heart rate and interaction
with this receptor subtype could then lead to
adverse effects.
Parasympathetic
pathway, vagus
Ach
Ach
m2
NA
b
Ach
m1
-
m2
-
m3
Pharmacological targets for the treatment of the overactive bladder,
the role of parasympathetic system
Anthicolinergic agents
Atropine, Propantheline, and other unselective muscarinic ligands, such as
selective M3 antagonists
Pirenzepina
Salifenacine, “Vescicare”
O
HN
N
N
O
N
N
N
O
O
O
HN
N
HN
O
Salifenacine
1-Phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester
N
Pirenzepine analog
Vescicare works by blocking the M3 receptor, which is primarily responsible for bladder
muscle contraction.
It is a potent muscarinic receptor antagonist that helps reduce incontinence episodes,
increases the amount of urine the bladder can hold, reduces the frequency of urination
episodes, and decreases the pressure or urgency associated with the urge to urinate.
Launch of Orally Disintegrating Tablet of Staybla® Tablets 0.1mg, a Drug for Overactive Bladder
Imidafenacin is a novel anticholinergic agent exerting selective antagonist activity on M3 and M1 muscarinic subtype
receptors, and improves urgency of urination, pollakiuria and urge urinary incontinence associated with OAB. It has been
highly regarded that the drug can improve the quality of life (QOL) of the patients with OAB because it selectively acts on
the bladder and therefore incidence of dry mouth is rather small.
4-(2-Methyl-1-imidazolyl)-2,2-diphenylbutanamide
New therapies for OAB
Nicotinic receptor blokers
Nicotinic receptor blokers are essentially neuromuscular blockers (NMBs, also
known as skeletal muscle relaxants), these drugs with anaesthetics, hypnotics
and analgesics, constitute the major classes of drugs routinely used in
modern anaesthesia.
On the basis of their mechanisms of action, NMBs are divided into two
categories:
a) depolarizing
b) non-depolarizing
Most of the clinically used NMBs are nondepolarizing drugs
Mechanism of action of neuromuscular blockers
a)-Depolarizing NMBs act as agonists of the nAChR. They stimulate an initial
opening of the ion channel, producing contractions known as fasciculations.
However, since these drugs are broken down relatively slowly by cholinesterase
enzymes, compared to the very rapid hydrolysis of acetylcholine by
acetylcholinesterase (AChE), they bind to the receptor longer than acetylcholine.
This causes persistent depolarization and desensitization of the end-plate.
Succinylcholine is the only depolarizing NMB that is still in clinical use.
b)-Nondepolarizing Atracurium, mivacurium, pancuronium, vecuronium,
and rocuronium are competitive antagonists of the nicotinic acetylcholine
receptor (nAChR) at the neuromuscular junction.
By blocking the acetylcholine-induced activation of the ion channel, NMBs prevent
cell membrane depolarization, and as a result, the muscle becomes flaccid.
Natural ligand of the nAChR with competitive antagonist activity,
non depolarizing agent
O
+
N
OCH3
OH
*
O
H 3CO
OH
D-Tubocurarine
*
N
Nicotinc receptor blokers derived from the molecular model of
curare
H3CO
+N
H3CO
H
O
O
H3CO
OCH3
2
H
O
SO3-
OCH3
N+
O
H3CO
Atracuronio besilato
OCH3
OCH3
a)-Depolarizing NMBs, agonists of the nAChR
+ N
O
O
2Cl-
Succinilcoline
O
O
N +
The discovery of the neuromuscular blocking activity of
malouetine isolated from the roots and bark of Malouetia
bequaertiana Woodson by Quevauviller and Laine in 1960
who, showed that malouetine had similar neuromuscular
blocking activity to d-tubocurarine but was only one-third as
toxic, stimulated interest in aminosteroids as potential
neuromuscular blockers.
From malouetine to the drugs
b)-nondepolarizing NMBs,
competitive antagonists of the nAChR
H
Structural formulae of some synthetic
aminosteroids with neuromuscular blocking activity
H
H
5a-Androstano
OAc
N+
N+
H
AcO
OAc
H
H
Pancuronium bromide
N+
N
H
AcO
H
H
Vecuronium bromide
Examples of different protonation of the base
Medical manipulation of NMBs
At the end of surgery or a period of intensive care, a reversal agent of NMBs
(nondepolarizing comp. 3) is often administered to the patient to assist the
recovery of muscle function and/or to prevent residual neuromuscular block.
All clinically used reversal agents are AChE inhibitors, such as neostigmine, 1
and edrophonium 2, which inhibit the breakdown of acetylcholine to increase the
level of acetylcholine at the neuromuscular junction and to gain competitive
advantage for acetylcholine to bind to the nAChR (Figure 1B).
Nondepolarizing
Rocuronium Br-
competitive antagonists
reversal agents
Medical manipulation of neuromuscular blokers, NMBs
Side effects of reversal agents
The use of AChE inhibitors as NMB reversal agents has several drawbacks.
First of all, AChE inhibition causes nonselective potentiation of neurotransmission
to all synapses (both somatic and autonomic) involving acetylcholine, especially
those in the heart, and leads to many side effects including bradycardia,
hypotension, etc.
Therefore, in practice, these agents are often used in combination with a muscarinic
acetylcholine receptor (mAChR) antagonist such as ATROPINE or glycopyrrolate to
antagonize the muscarinic effects of acetylcholine in the autonomic parasympathetic
neuroeffector junctions (e.g., the heart).
Finally, since depolarizing NMBs (e.g., succinylcholine) are themselves cholinergic
agonists, AChE inhibitors are not suitable for the reversal of depolarizing NMBs.
Fine presentazione Ach seconda parte