Nervous System

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Transcript Nervous System

Examples of cellular communications present in mammals

•

Endocrine

Autocrine Paracrine

•

Neurocrine

Endocrine communication by the medullary secretions

•

Endocrine

Endocrine communication

Autocrine Paracrine

•

Neurocrine

Zona glomerulare mineralcorticoidi (aldosterone) “ fascicolata glucocorticoidi (cortisolo) “ reticolata androgeni surrenalici (testosterone) “

midollare

adrenalina (autacoide)

Location of the major endocrine glands in the body

• Endocrine secretion

Differenziazione anatomica del tessuto dei surreni

Adrenal cortex

The

adrenal medulla

is part of the adrenal gland, it is composed of c

hromaffin cells

neuroendocrine cells found in the medulla of the adrenal gland (suprarenal gland, located above the kidneys) and in other ganglia of the sympathetic nervous system.

It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete

epinephrine

norepinephrine

, and a small amount of

dopamine

in response to stimulation by sympathetic preganglionic neurons.

Biosynthesis of catecholamines

La preparazione dell ’ autacoide nel tessuto della midollare

Neurocrine seceretion and communication

Neurocrine communication

•

Endocrine

Autocrine Paracrine

•

Neurocrine

Struttura delle cellule neuronali

Differenziazione del sistema nervoso centrale (cervello e midollo spinale) e del sistema nervoso periferico

Autonomic Nervous System:

sympathetic division

THE AUTONOMIC sympathetic NERVOUS SYSTEM

Sympathetic System

Short preganglionic fibers Peripheral ganglia lie distant target organs Dal midollo spinale i neuroni confluiscono prevalentemente nei gangli paravertebrali o anche in alcuni gangli prevertebrali con diverse connessioni e con fibbre postgangliari raggiungono gli organi.

Ach and Dopamine

Peripheral activities of sympathetic nervous system involve many organs:

heart, bladder,pupils, bronchi, vessels, glands

Esempi di comunicazione neuronale

The arrival of the action potential causes the release of chemical messengers from the terminal endings of the axon

Different Types of NTs

The neurotrasmitter of sympathetic system

Monoamines a.

Catecholamines i.

Dopamine b.



Norepinephrine

Indoleamines i.

Serotonin Amine Acetylcholine (Ach) 3.

Amino Acids a.

Glutamate b.

Peptides Aspartate GABA Glycine

Discovery of the neurotrasmitter

In the mid-1950s, central nervous system (CNS) and was found to constitute ca

5% of the total catecholamine content in the mammalian brain.

Epinephrine

was discovered in the Soon thereafter it was shown that peripheral CNS

Epinephrine Epinephrine

did not cross the blood-brain barrier (BBB) but that was being synthesized in the brain.

Some deseases related to the neurotrasmitter

CNS

Epinephrine

has been implicated in some of the neurodegeneration seen in

Alzheimer's disease,

as well as in the

regulation of blood pressure, respiration, body temperature,

and the

modulation of behaviour.

Central and peripheral neurotrasmitter of the adrenergic system

Norepinephrine



Also known as noradrenaline (NA).



Neurons that release NE are organized into 3 main clusters in the brainstem: locus coeruleus in the pons, the lateral tegmental system of the midbrain, and the dorsal medullary group .



Noradrenergic cells of locus coeruleus are believed to modulate behavioral and physiological processes.

Catecholamine pathways in the CNS

Caratterizzazione anatomica delle vie neuronali di tipo simpatico in alcune regioni del SNC

Biosynthesis of catecholamines

La biosintesi dei neurotrasmettitori

I substrati biologici di interazione del neurotrasmettitore e/o dell ’ autacoide

Interlocutori chimici nella comunicazione cellulare

Metabotropic receptors or GPCRs

Ligands

of GPCRs.

They bind to a specific site on these proteins, through a "lock and key" style interaction, i.e. the shape of the molecule fits a complementary pocket in the receptor.

Primary sequence of receptor protein

Proposed mechanism of ligand-receptor interaction

La subunità a del trimero presenta una tasca di legame per i nucleosidi guaninici: GDP e GTP GDP GTP

What is the EFFECTOR inside the cell?

Depending of the type of G-protein ( a s , a i / o ) we can observe:

Depending of type of G-protein ( a q / 11 ) we can observe: Phospholipase C DAG PIP 2 IP 3

Quali sono le proteine recettoriali del sistema adrenergico ?

Anatomic distribution of the receptors interacting with catecholamines

1 -receptors binding second messengers.

Gq

protein activating inositole triphosphate and diacylglycerole as Subclasses of

1 -receptors are discovered:

1 a

,

1 b

, and

1 d

.

Il recettore alfa-adrenergico attiva la fosfolipasi-c, via blu nello schema

Anatomic distribution of the receptors interacting with catecholamines



receptors binding Gs-protein, activating cAMP as a second messenger

Il recettore beta1-adrenergico attiva la adenilato ciclasi

Anatomic distribution of the receptors interacting with catecholamines



2 receptors binding the Gi/s-protein, with a modification of cAMP as second messenger.

Il recettore beta2-adrenergico Attiva/disattiva la adenilato ciclasi

Anatomic distribution of the receptors interacting with catecholamines

2 -receptors: binding the Gi-protein, restraining the adenylcylase system, cAMP as second messenger

Recent evidences suggest that

2 adrenoreceptor has been further divided into the

2A,

2B,

2C subtypes.

2A subtype is considered involved in antinociception ( agonists ), while hypertensive resposes are belived to be mediated through the

2B subtype, and several other CNS responses are attributed to the

2C .

Il recettore alfa2-adrenergico disattiva la adenilato ciclasi

Anatomic distribution of the receptors interacting with catecholamines



3 receptors: binding the adenylate cyclase stimulating Gi-protein, cAMP as second messenger

La struttura chimica delle sostanze biologicamente attiva

Struttura chimica delle e catecholamines

OH NH 2 N HC H 3 HO OH

4-(2-amino-1-idrossi-etil)-benzene-1,2-diolo

H O OH

4-(1-idrossi-2-metilamino-etil)-benzene-1,2-diolo

OH OH OH OH H H H OH 3 1 HO Ar 4 H NHR 2

(R)-nor- and adrenaline

H HO H H NH 2

R-

NH 2

S+

Binding of physiological ligands (NA and A) to the protein receptors

Neurotransmitters and hormones

act by producing changes in the conformation of the receptor they bind to, this conformational change leads to activation of signal transduction pathways indirectly via G-proteins. In the case of adrenoceptors, these proteins have seven transmembrane domain spanning helicies (numbered I-VII), which aggregate together into a rough cylinder with a pore in the centre.

Noradrenaline and Adrenaline bind on the inside of this pore.

The metabolism of catecholamines

The COMT enzyme

The enzyme that catalyzes the

-methylation of catecholamine is the

Catechol-O-methyltransferase

(

COMT

; EC 2.1.1.6), which uses

S-adenosyl-L-methionine

(SAM) as the methyl donor. The physiological substrates of COMT include a wide variety of organic chemicals, such as catecholamines (dopamine,

norepinephrine

, and

epinephrine

), catechol estrogens, dihydroxyindolic intermediates of melanin, and many others. In addition, many medicinal products, such as triphenols and substituted catechols, dobutamine, isoprenaline, rimiterol, levodopa, benserazide, dihydroxy-phenyl serine, and dihydroxy derivatives of tetrahydroxy-isoquinolones, are also substrates of COMT.

NH 2

COMT

HO OH

Catechol-O-methyltransferase

COMT S-Adenosyl methionine

Cartoon diagram of human COMT in complex with an

inhibitor

(dark blue) and

S-adenosyl methionine (SAM, yellow), the methyl donor.

The metabolism of catecholamines

NH 2

MAO

HO OH

Both

types of MAOs live in the

brain

, but they hang out in different kinds of cells. MAO-B is found in

catecholaminergic neurons

, while MAO-A is found in

serotonergic neurons.

As we travel further down in the body, we will find the MAO-A is localized in the

placenta, liver,

and

gastro-intestinal tract

, but MAO-B is found spread out in the body in

blood platelets

and the

central nervous system

Monoamine oxidase, MAO

S H 2 C H 3 C R N N

FAD

N O NH O

Ribbon diagram of a monomer of human

MAO-A

, with

FAD

and an inhibitor bound, oriented as if attached to the outer membrane of a mitochondrion.

MAO activity In the degradation of catecholamines by MAO, hydrogen peroxide could be oxidized to make free radicals.

Hydrogen peroxide is normally removed by glutathione peroxidase, but whenever iron is associated with neuromelanin, it will donate an electron to the hydrogen peroxide, which will then divide into hydroxyl radical (*OH) and hydroxyl ion (OH-). The hydroxyl radicals are extremely toxic to brain tissue.

The purpose of MAO-inhibitors is to block the formation of hydrogen peroxide so that these radicals cannot be made.

Possibili applicazioni terapeutiche del sistema adrenergico

Adrenergic implication in blood pressure regulation

Blood Pressure Regulation

Sympathetic nervous control

’

ADRENALINA

come farmaco Epinephrine ampoule, 1 mg (Suprarenin) Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding.

It has been used historically for bronchospasm and hypoglycemia.

A natural sympathetic molecular model

OH NHCH 3 Ephedrine (R,S) (-)2-Methylamino-1-phenyl-propan-1-ol L-ERYTHRO (R,R) and (S,S) Pseudoephedrine Botanical: Ephedra vulgaris

The (1

)- and (1

)-enantiomers are designated EPHEDRINE.

The isomer which is marketed is (-)-(1 R ,2 S )-ephedrine

Another sympathetic molecular model discovered in “

Claviceps purpurea

”

H N H O R N H R = HN OH HN

Simple amide

R= HN O OH N N O O OH

Amide derived from cyclic tripeptide

Rappresentazione figurativa di manipolazioni molecolari

Adrenergic therapy avoiding CNS

Partially associated with the compounds of the medullary

Adrenergic receptor agonists selective for the

a 1

or reverse the

hypotensive state

family have been used to prevent associated with a variety of medical conditions, they have also been used to treat

nasal congestion, mydriasis, and disorders of the lacrimal gland.

-adrenergic receptor agonists with

phenylethyamine

structure

OH H N OH OH

Phenylephrine

3-(1-Hydroxy-2-methylamino-ethyl)-phenol H 3 CO OCH 3 OH NH 2 CH 3

Methoxamine

2-Amino-1-(2,5-dimethoxy-phenyl)-propan-1-ol Racemo TREO HO

Synephrine

4-(1-Hydroxy-2-methylamino-ethyl)-phenol

Nor-Adrenaline

OH NH 2 HO OH OH NH 2 CH 3

Metaraminol

OH TREO(R,S) 3-(2-Amino-1-hydroxy-propyl)-phenol

-adrenergic receptor agonists with

phenylethyamine

structure

Nor-Adrenaline

OH NH 2 HO OH OH H 3 CO NH 2 O OCH 3

Midodrine

2-Amino-

-[2-(2,5-dimethoxy-phenyl)-2-hydroxy-ethyl]-acetamide

Des-

gly

-midodrine Midodrine is a prodrug which forms an active metabolite, des-gly-midodrine, which is an α 1 -receptor agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Des-gly-midodrine does not stimulate cardiac  -adrenergic receptors, it diffuses poorly across the blood–brain barrier, and is therefore not associated with effects on the central nervous system.

Natural substance stimulant of the sympathetic system OH NHCH 3 Ephedrine (R,S) (-)2-Methylamino-1-phenyl-propan-1-ol L-ERYTHRO OH OH NH 2 CH 3

Metaraminol, a synthetic compound

Botanical: Ephedra vulgaris

The (1

)- and (1

)-enantiomers of ephedrine are designated pseudoephedrine OH NHCH 3

+ (1

)-2-methylamino-1-phenylpropan-1-ol

OH NHCH 3 Pseudoephedrine

(commonly abbreviated as PSE) is a sympathomimetic amine commonly used as a decongestant .

Pseudoephedrine is a phenethylamine , and a diastereomer of ephedrine.

The salts

pseudoephedrine hydrochloride

and

pseudoephedrine sulfate

are found in many over-the-counter preparations either as single-ingredient preparations, or more commonly in combination with antihistamines , paracetamol (acetaminophen) and/or ibuprofen .

The advantage of oral pseudoephedrine over topical nasal preparations, such as oxymetazoline , is that it does not cause rebound congestion ( rhinitis medicamentosa ); however, it is more likely to cause adverse effects including hypertension .

Pseudoephedrine is being phased out as an over-the-counter drug and replaced by alternative decongestants like

phenylephrine

, due pseudoephedrine's extreme popularity as a precursor in the illicit synthesis of methamphetamine.

Summary of adrenergic agonist design with

phenylethylamine

structure

Substituted phenyl-

SPACER

amino function

General structure

R R OH R' H N R"

a 1

adrenergic receptor agonists with

imidazoline

structure

N HN

Naphazoline

2-Naphthalen-2-ylmethyl-4,5-dihydro-1

-imidazole N HN

Tetrizoline

2-(1,2,3,4-Tetrahydro-naphthalen-1-yl)-4,5-dihydro-1

-imidazole N HN

Xylometazoline

2-(4-

tert

-Butyl-2,6-dimethyl-benzyl)-4,5-dihydro-1

-imidazole

“

Otrivin

” , decongestionante nasale NOVARTIS

Nor-Adrenaline

OH NH 2 OH HO N HN

Oxymetazoline

2-(4-

tert

-Butyl-2,6-dimethyl-benzyl)-4,5-dihydro-1

-imidazole

Summary of adrenergic agonists designed with

imidazoline

structure

Substituted phenyl

SPACER

General structure

imidazoline function

R R HN N

Design of

1 /

2 adrenergic agonists

Autonomic nervous system effects

2 -receptors: binding the inhibitory G-protein, restraining the adenylcylase system, cAMP as second messenger

Recent evidences suggest that

2A sybtype is considered involved in antinociception ( agonists ), while hypertensive resposes are belived to be mediated through the

2B the

2C .

adrenoreceptor has been further divided into the

2A,

2B,

2C subtypes.

subtype, and several other CNS responses are attributed to

Autoreceptors in the BRAIN, in particular in the locus coeruleus, regulate transmitter release in the anterior cortex

Adrenergic and other receptors in blood pressure regulation,

marginal implication of a2 and b2 in the vessel

R R

Design of

2 /

adrenergic agonists

Substituted aromatic

SPACER

imidazoline function

HN N R R H N HN N

Adrenergic receptor agonists for the

receptor family

Cl H N H N Cl N

Clonidine

(2,6-Dichloro-phenyl)-(4,5-dihydro-1

-imidazol-2-yl)-amine Cl H N H 2 N Cl N

Apraclonidine

2,6-Dichloro-

-(4,5-dihydro-1

-imidazol-2-yl)-benzene-1,4-diamine

Local use of the

a 2

agonist in the treatment of glaucoma

PILOCARPINA ECOTIOPATE TIMOLOLO* ACETAZOLAMIDE*

CLONIDINA e analoghi LATANOPROST*

*also in association

agonista muscarinico ag. muscarinico e inibitore AchE antagonista  -adrenergico Inibitore CA Agonisti a 2 adrenergici analogo prostaglandinico

Centrally acting drugs for reducing sympathetic outflow of the brain

H 3 CO N H N

PHYSIOTENS®,

moxonidine

N Cl N (4-Chloro-6-methoxy-2-methyl-pyrimidin-5-yl)-(4,5-dihydro-1

-imidazol-2-yl)-amine Moxonidine

binds to “ proposed

imidazoline

- binding site ” of the rostral ventrolateral medulla of the brain stem.

PHYSIOTENS®

works in the brain, where blood pressure is regulated.

Beta-1 agonists are useful drugs?

Parzial beta-1 adrenergic compounds not in therapeutic use

DESIGN OF BETA-BLOCKERS compounds

•Sostituzione delle funzioni catecoliche •Introduzione di uno spacer tra l ’ aromatico e il gruppo etilaminico nella catecolamina

Xamoterol O OH H N HO

Prenalterolo parz. agonista

Partial agonist activity

The medullary activity La

Dopamina

in periferia manifesta una attività dose dipendente: 1.Attività a livello renale, natriuresi 2.Attività a livello cardiaco di tipo positivo 3.Attività sul circolo La

DOBUTAMINAè

un farmaco simpaticomimetico utile per sostenere il cuore nelle relative patologie (

RS)-4-(2-{[4-(4-hydroxyphenyl)butan-2-yl]amino}ethyl)benzene-1,2-diol

The

adrenal medulla

is part of the adrenal gland, it is composed of c

hromaffin cells

neuroendocrine cells found in the medulla of the adrenal gland (suprarenal gland, located above the kidneys) and in other ganglia of the sympathetic nervous system.

It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete

epinephrine

norepinephrine

, and a small amount of

dopamine

response to stimulation by sympathetic preganglionic neurons.

Design of

2

adrenergic agonists

A tentative to induce more beta-adrenergic selectivity

OH H N H O OH (R)-isoproterenol Extracellular stereoview of the (R)-isoproterenol complex with de novo



-2-AR model. The ligand is displayed in white, and key binding site residues are shown in magenta. Hydrogen bonds are represented with dashed yellow lines. Key contacts include a charge reinforced hydrogen bond between the protonated amine and D113 in TM3, hydrogen bonds between the catechol hydroxyls, mOH and pOH, with S204 and S207 in TM5, and a hydrogen bond between ligand side-chain hydroxyl and N293 in TM6. The ligand also makes van der Waals contact with V114 in TM3, F289 in TM6, and N312 in TM7.

Adrenergic receptor agonists for the

 2  2

receptor family.

agonists are the most effective bronchodilators available and are relatively free of unwanted effects.

L ’ alchilazione della funzionalità amminica è importante per indurre una maggiore attività di tipo  agonista o antagonista

OH NH H O OH NH H O OH

Isoprenaline agonist

Orciprenaline

5-(1-Hydroxy-2-isopropylamino-ethyl)-benzene-1,3-diol

Short-acting



2 agonists

OH OH NH H O NH OH

Terbutaline

5-(2-tert-Butylamino-1-hydroxy-ethyl)-benzene-1,3-diol H O H O

Salbutamol or Albuterol

4-(2-tert-Butylamino-1-hydroxy-ethyl)-2-hydroxymethyl-phenol

OH NH

Long-acting



2 agonists

OH H O NH-SO 2 -CH 3

Soterenol

N-{5-[2-(isopropylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methansolphonamide H N

H O OCH 3 NH OHC

Formoterol

racemo R/R-S/S

N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide H O OH H N OH OH

Fenoterol

Brand Name(s): Alupent; Bricanyl Turbuhaler

; racemo R/R-S/S

1-(3,5-Dihydroxyphenyl)- 2-[(RS)-2-(4-hydroxyphenyl)- 1-methylethylamino]ethanol These drugs are used for the treatment of asthma and congestive heart failure

Long-acting



2 agonists

OH H N O H O H O

Salmeterol

2-Hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenyl-butoxy)-hexylamino]-ethyl}-phenol

Perspectives There are currently two marketed long-acting β2-adrenoreceptor agonists (LABAs), However, neither of these agents are approved for once-daily dosing.

salmeterol

and

formoterol

which exhibit sufficient duration of action to support twice-daily dosing regimens following inhaled delivery.

Indacaterol

is the most advanced agent, having been recently approved as its maleate salt in the European Union (2009) and launched (2010)

for once-daily treatment

OH H N HO HN O 5-((R)-2-(5,6-diethyl-2,3-dihydro-1H-inden-2-ylamino)-1-hydroxyethyl)-8-hydroxyquinolin 2(1H)-one

The Pfizer once-daily candidate is:

OH H N HO NHSO 2 M e O H N OH

Other application, tocolitic drug

Ritodrine hydrochloride

results in inhibition of uterine contractility.

(Yutopar), stimulates 

receptors of smooth muscle of the uterus, which

OH H N OH H N H O H O OH (R,S) (ERYTHRO) 1-(4-idrossiphenyl)-2-



2-(4-idrossiphenyl)-etilamino



-propanolo

Synephrine

Isoxsuprine hydrochloride

, (

Vasodilan, Voxsuprine)

Isoxsuprine is in a class of drugs called vasodilators. Isoxsuprine relaxes veins and arteries, which makes them wider and allows blood to pass through them more easily. The activity is mainly due to  -2 receptor vasodilatation.

These actions may help treat the symptoms of conditions such as cerebral vascular insufficiency (poor blood flow to the brain), arteriosclerosis (hardening of the arteries), Raynaud's phenomenon, and other conditions involving poor blood flow in the veins and arteries.

OH H N O HO 4-(2-(1-phenoxypropan-2-ylamino)-1-hydroxypropyl)phenol

1 -antagonists have been used for the treatment of hypertension

Alpha-adrenoceptor blocking drugs Prazosin

has post-synaptic alpha-blocking and vasodilator properties and rarely causes tachycardia. It may, however, cause a rapid reduction in blood pressure after the first dose and should be introduced with caution.

Doxazosin

, and

terazosin

have properties similar to those of prazosin.

Alpha-blockers may be used with other antihypertensive drugs in the treatment of hypertension.

O N O H 3 CO N N H 3 CO N NH 2

Prazosin

[4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-furan-2-yl-methanone OH H N HO OH

adrenaline

Alpha-adrenoceptor blocking ligands as antihypertensive drugs O N O H 3 CO N N H 3 CO N NH 2

Terazosin

[4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(tetrahydro-furan-2-yl)-methanone O O N H 3 CO N N O H 3 CO N NH 2

Doxazosin

[4-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone

O N O H H 3 3 CO CO N N NH 2 N Structure activity studies

(SAR) of a -antagonists with quinazoline function more important function:

Nitrogen in position 1 of quinazoline

Two methoxy groups in position 6 and 7

The amino function in position 4

The carbonyl group outside the quinazoline nucleous

The more recent cloning and expression of a

1a ,

1b , and

receptor subtypes have allowed the search for compounds with selectivity for individual subtypes within the a

family.

The efficacy of

a1-a/d

antagonists in the treatment of benign prostatic hyperplasia has been demonstrated, the role of the regulation of blood pressure has recently been advanced, while a potential therapeutic use for the a1-d a1-b subtype in the subtype has not been firmly established.

Benign Prostatic Hypertrophy, BPH

Prostate size increases with age

Prostate growth is hormonally regulated

1.Testosterone is converted to Dihydrotestosterone 2.

Dihydrotestosterone

stimulates prostate growth 3.

Estrogen

also stimulates prostate growth

Alpha-adrenoceptor blocking drugs

Doxazosin, prazosin and terazosin

are also indicated for benign prostatic hyperplasia

Alfuzosin

is a tentative to improve a 1 A selectivity to treat BPH, obtained with TAMSULOSINE.

H 3 CO N N N H N O O H 3 CO

Alfuzosin

Tetrahydro-furan-2-carboxylicacid{3-[(4-amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-propyl}-amide

A selective antagonist of prostatic adrenergic receptors

Phenyethylamine derivatives

H N O OH H N H 3 CO SO 2 NH 2 O

Tamsulosin

(R) 5-{2-[2-(2-Ethoxy-phenoxy)-ethylamino]-propyl}-2-methoxy-benzenesulfonamide The most selective

1a antagonist HO OH

adrenaline

A new selective antagonist of prostatic adrenergic receptors

SILODOSINA 1-(3-hydroxypropyl)-5-[(2

R)-({2-[2-[2-(2,2,2 trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7 carboxamide

La silodosina è un potente antagonista dei recettori adrenergici a e in particolare ha una affinità molto elevata per il sottotipo a 1a.

Il blocco del recettore a 1a provoca un rapido aumento del flusso urinario ed un miglioramento dei sintomi dovuti all ’ iperplasia prostatica benigna.

Il farmaco è un prodotto originale della ditta farmaceutica giapponese KIESSEI, in Europa è commercializzato da RECORDATI tramite NYCOMED

Benign Prostatic Hypertrophy, BPH

Prostate size increases with age

Prostate growth is hormonally regulated

1.Testosterone converted to Dihydrotestosterone 2.Dihydrotestosterone stimulates prostate growth 3.Estrogen also stimulates prostate growth Steroid 5 a reductase (EC 1.3.99.5) is a membrane-bound,

NADPH-

dependent enzyme that catalyzes the selective, irreversible reduction of 4-ene-3-oxosteroids to the corresponding 5 a -3-oxosteroids.

Two isoforms of the enzyme, types I and II, are known to exist

. The two forms have only 50% amino acid homology and are found in differing regions in the body.

Type I

is found in skin tissues, including the scalp.

Type II

is found mainly in genitalia tissues, including the prostate and skin of the genitalia.

La riduzione del testosterone a diidrotestosterone, è biologicamente determinata dalla 5 a steroido reduttasi umana il cui cofattore è il

NADH/NADPH

NADP + +H + +2e ____ > NADPH

Reduction of prostate hyperplasia via 5

reductase inhibition

Inhibition of Testosterone to Dihydrotestosterone conversion

1.Competitive inhibition of enzyme 5 a -reductase

2. Reduces volume of prostate and improves urine blood flow

inhibits Type II 5

reductase

Dutasteride inhibits both Type I and II 5

reductase

Finasteride (Propecia®)

androstano

[(5

, 17



-N-(1,1-dimethyl-ethyl) -3-oxo-4-azaandrost- 1-ene-17-carboxamide) Finasteride

has higher affinity for

5a -R type II

(IC50 = 9.4 nM) versus Type I (IC50 = 410 nM).

L ’ attività inibitoria della

FINASTERIDE

è stata attribuita sia alla somiglianza strutturale con il testosterone che le permette di legarsi in modo non covalente all ’ enzima e di essere ridotta a

Diidro-finasteride

al posto del testosterone che alla sua capacità di legare il cofattore NADPH formando un legame covalente che si traduce in un

NADP-diidrofinasteride

che lentamente libera la diidrofinasteride.

Adverse effects

Sexual effects were the most common type of adverse reaction, decreased libido (5% in the finasteride group and 3% in the placebo group), erectile dysfunction (8% finasteride, 3% placebo), and ejaculation disorder (2% finasteride, 0.6% placebo).

Anxiety and depression Other 5a-reductase substrates include progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone.

3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effect on cerebral function by enhancing gamma-aminobutyric acid GABAergic inhibition. These neuroactive steroid derivatives enhance GABA at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.

Progesterone

Steroid 5 a reductase 3α-hydroxysteroid dehydrogenase

5α-Dihydroprogesterone Allopregnanolone

An overlay of molecular models of finasteride (purple) and testosterone (yellow).

SAR of Finasteride

Dutasteride ([5

, 17



-N-(2,5-trifluoromethyl-phenyl) -3-oxo-4-azaandrost- 1-ene-17-carboxamide) ([5

, 17



-N-(1,1-dimethyl-ethyl) -3-oxo-4-azaandrost- 1-ene-17-carboxamide)

Beta-adrenoceptor blocking drugs

(



-blockers) block the beta-adrenoreceptors in the heart, peripheral vasculature, bronchi, pancreas, and liver.

Principal therapy

ANGINA

By reducing cardiac work beta-blockers improve exercise tolerance and relieve symptoms in patients with

angina.

MYOCARDIAL INFARCTION

Several studies have shown that some beta-blockers can reduce the recurrence rate of

myocardial infarction

HYPERTENSION

Beta-blockers are effective antihypertensives but their mode of action is not understood; they reduce cardiac output, alter baroceptor reflex sensitivity, and block peripheral adrenoceptors.

ARRHYTHMIAS

Beta-blockers act as

anti-arrhythmic drugs

principally by attenuating the effects of the sympathetic system on automaticity and conductivity within the heart.

HEART FAILURE

Beta-blockers may produce benefit in heart failure by blocking sympathetic activity.

OTHER USES

Beta-blockers have been used to alleviate some symptoms of

anxiety

, are also used in the

prophylaxis of migraine

, and some are used topically in

glaucoma

Pharmacokinetic of



-blokers

Some



-blokers

have intrinsic sympathomimetic activity (

ISA

), they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities.

Many beta-blokers have membrane-stabilizing activity (quinidine-like activity) , the capacity of



-blockers to depress most cardiac tissues by a direct action on cardiac cells and are used for the management of arrhythmia only.

Some beta-blockers are

lipid soluble

and some are

water soluble

. The most water-soluble are less likely to enter the brain, and may therefore cause less sleep disturbance and nightmares. Water-soluble beta-blockers are excreted by the kidneys, they accumulate in renal impairment and dosage reduction is therefore often necessary.

Beta-blockers with a relatively

short duration of action

have to be given two or three times daily, many of these are, however, available in modified-release formulations so that administration once daily is adequate for hypertension. Some beta-blockers

have an intrinsically longer duration of action and need to be given only once daily.

Other pharmacological activities:

-antagonist activity

Many

beta-blockers have, in addition, an arteriolar vasodilating action, by diverse mechanisms, and thus lower peripheral resistance. There is no evidence that these drugs have important advantages over other beta-blockers in the treatment of hypertension.



-

selectivity

Many

beta blokers have less effect on the 

-2

(bronchial) receptors and are, therefore, relatively

cardioselective

, they have a lesser effect on airways resistance but are

not

this side-effect. free of

L ’ alchilazione della funzionalità amminica è importante per indurre una maggiore attività di tipo  agonista o antagonista

OH H N HO OH

Isoprenalina o Isoproterenolo ag.

La sostituzione delle due funzioni fenoliche con alogeni riduce l ’ attivazione del recettore

OH H N OH H N HO OH

Terbutil-noradrenalina ag.

Cl Cl

Dicloroisoprenalina parziale ag.

In termini chimici la sostituzione del gruppo OH con il Cl aumenta il volume del sostituente e ne riduce la polarità

•Sostituzione delle funzioni catecoliche con altri gruppi •Introduzione di uno spacer tra l ’ aromatico e il gruppo etilaminico nella catecolamina

OH H N O OH H N HO

Prenalterolo parz. agonista Pronetalolo parz. agonista

Il Pronetalolo è un  antagonista senza nessuna attività residua, i trials clinici hanno pero ’ dimostrato che induce tumori del timo ed è stato dismesso

ArO 2 1 4 NHR 3

The first



-bloker,

used therapeutically from 1964 in patients with angina pectoris and myocardial infarction and also effective in hypertension and irregularities of heart beat O OH H N

Propranololo

3-Isopropylamino-1-(naphthalen-1-yl-oxy)-propan-2-ol

Pindolol

has intrinsic sympathomimetic activity

they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities.

O OH H N HN pindolol 1-(1H-Indol-4-yl-oxy)-3-isopropylamino-propan-2-ol

Acebutol

has intrinsic sympathomimetic activity

they tend to cause less bradycardia than the other beta-blockers and may also cause less coldness of the extremities.

O O OH H N N H O acebutol N-[3-Acetyl-4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-butyramide

Atenolol

, is one of

the most water-soluble, it has less likely to enter the brain, and may therefore cause less sleep disturbance and nightmares. Water-soluble beta-blockers are excreted by the kidneys, they accumulate in renal impairment and dosage reduction is therefore often necessary.

O O OH H N H 2 N

atenolol

2-[4-(2-Hydroxy-3-isopropylamino-propoxy)-phenyl]-acetamide

Metoprolol ,

has an intrinsically longer duration of action

and need to be given only once daily.

O OH H N O

metoprolol

1-[4-(2-methoxy-ethyl)-phenoxy]-3-isopropylamino-propan-2-ol



-Blokers without oxymethylene

“

SPASER

”

OH HO CONH 2

Labetalol

2-Hydroxy-5-[1-hydroxy-2-(1-methyl-3-phenyl-propylamino)-ethyl]-benzamide OH H N O S O N H

sotalol

N-[4-(1-Hydroxy-2-isopropylamino-ethyl)-phenyl]-methanesulfonamide

Sotalol is used specifically as an antiarhythmic drug.

OH H N O S O N H

sotalol

Sotalol is a non selective competitive β-adrenergic receptor blocker

Sotalol is also classified a Class III agents for the treatment of tachyarrythmia

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.

Drugs include: amiodarone, ibutilide,

sotalol

, dofetilide, and dronedarone.

Labetalol, carvedilol

are beta-blockers which have, in addition, an arteriolar vasodilating action by diverse mechanisms, and thus lower peripheral resistance.

OH HO CONH 2

labetalol

2-Hydroxy-5-[1-hydroxy-2-(1-methyl-3-phenyl-propylamino)-ethyl]-benzamide OH O H N O OCH 3 HN

carvedilol

1-(9H-Carbazol-4-yl-oxy)-3-[2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol

Atenolol, betaxolol, bisoprolol

effect on the  2 and (to a lesser extent)

acebutol

, have less (bronchial) receptors and are, therefore, relatively

cardioselective.

Beta blokers with specific application O OH H N H 3 COOC

esmolol

3-[4-(3-isopropilamino-2-hydroxy-propy-ossi)-phenyl-propionic acid methyl ester

ESMOLOL therapy indication

For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a

short-acting agent

is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention.

Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes.

In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases.

At therapeutic dosages,

esmolol

(quinidine-like) activity (MSA).

does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing

Beta blokers with specific application, for treatment of glaucoma O N O OH H N N S N

timolol

3-(tert-butylamino)-1-[(4-morpholin-4yl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol

Timolol

(timolol maleate ophthalmic gel) is a non-selective



-adrenergic receptor blocking agent.

Prostanoids for the treatement of glaucoma Prostaglandin analogues with specific application in the management of ocular hypertension

Prostaglandin F2α (Dinoprost)

, dinoprost, is a naturally occurring prostaglandin used in medicine to induce labor and as an abortifacient, it is produced by the uterus when stimulated by oxytocin.

Latanoprost is a prostaglandin F 2

analogue used topically (as eye drops) to control the progression of glaucoma

Isopropyl-(Z)-7[(1R, 2R, 3R, 5S)3, 5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate

Xalatan®/ XALACOM

XALACOM

è composto da:

latanoprost e timololo maleato

Questi due componenti riducono la pressione intraoculare elevata (PIO) con meccanismi d ’ azione diversi e l ’ effetto combinato porta a una maggiore diminuzione della PIO rispetto ai componenti somministrati singolarmente.

Latanoprost

, un analogo della prostaglandina F 2 a agonista selettivo del recettore prostanoide FP, riduce la PIO aumentando il deflusso dell ’ umore acqueo. Il meccanismo d ’ azione principale consiste nell ’ aumento del deflusso uveosclerale. E ’ stato inoltre riportato nell ’ uomo un aumento nella facilit à di deflusso (riduzione della resistenza al deflusso trabecolare). Latanoprost non ha un effetto significativo sulla produzione di umore acqueo, sulla barriera emato-acquosa o sulla circolazione sanguigna intraoculare.

Timololo

è un farmaco bloccante i recettori  -1 e  -2 adrenergici (non selettivo) privo di significativa attivit à simpaticomimetica intrinseca, come pure di effetto sedativo diretto a livello del miocardio e di attivit à stabilizzante di membrana. Timololo abbassa la PIO diminuendo la formazione di umore acqueo nell ’ epitelio ciliare . L ’ esatto meccanismo d ’ azione non è stato stabilito chiaramente, ma è probabile l ’ inibizione della sintesi di AMP ciclico causata da stimolazione endogena  -adrenergica.

Prostanoid analogues for the treatement of glaucoma

Bimatoprost, 7-[3,5-dihydroxy-2- (3-hydroxy-5-phenyl-pent-1-enyl)- cyclopentyl]-N-ethyl-hept-5-enamide Travoprost, propan-2-yl 7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-but-1-enyl]-cyclopentyl]hept-5 enoate

Nervous System

Central Nervous System (CNS)

(Brain and Spinal Cord) Peripheral Nervous System (PNS)

Efferent (motor) Nerves

( Transmit information to the perifery of the body)

Afferent (sensory) Nerves

(Carry sensory information to the CNS from the perifery of the body)

Autonomic Sympathetic Somatic Parasympathetic



Peripheral Nervous System (PNS)

•

Efferent (motor) Nerves

– Transmit information to muscles or glands

.

Somatic Nervous System

Stimulates Skeletal muscles



Autonomic Nervous System

•Stimulates Glands and Organs (e.g. heart) •Sympathetic

- Adrenergic – stress response

•Parasympathetic

- Cholinergic – basic functions

Autonomic Nervous System: parasympathetic division

THE AUTONOMIC NERVOUS SYSTEM

THE AUTONOMIC NERVOUS SYSTEM Parasympathetic System

Long preganglionic fibers Peripheral ganglia lie near target organs

Sympathetic System

Short preganglionic fibers Peripheral ganglia lie distant target organs

BRAIN

Ach and Dopamine

BRAIN

glands and organs NA ACh ACh Placca neuromuscolare

BRAIN

Nella midollare del surrene la norepinefrina viene metilata alla funzione amminica enzimaticamente ad

EPINEFRINA

The terminal step in Epi (

) biosynthesis is catalyzed by the enzyme

PNMT

whereby an activated methyl group from AdoMet (

) is transferred to NE (

) to produce Epi (

) and AdoHcy (