Lezione del 29/04/2005

Anno accademico 2004/05

Goodman&Gilman’s

melatonina

5-HT N-acetilase

o-metil-transferasi

Sintesi e metabolismo della serotonina

Il terminale serotoninergico

Recettori e meccanismi di trasduzione intracellulare

• Esistono almeno 7 tipi di recettori serotoninergici, suddivisi in alcuni sottotipi.

• I recettori sono per lo più associati a proteine G (7 domini transmembrana).

• Il recettore di tipo 3 (5-HT3) è un recettore canale che trasporta cationi (Na+, K+ con una simile permeabilità, ma può trasportare anche Ca2+)

Recettori serotoninergici

Comparison of the percentage amino acid identity between the different human 5-HT

receptor subtypes

Principali recettori 5-HTNome Effettore Distribuzione Patologia Funzione

5-HT1A Gi/cAMP↓

Go/Ca2+↑

Ippocampo, setto Ansia, ipertensione

Autorecettore

5-HT1B Gi/cAMP↓

Go/Ca2+↑

Striato, Ippocampo vasi, TSSA

Ansia Depressione

Comp.aggres

Autorecettore

5-HT1D Gi/cAMP↓

Go/Ca2+↑

(***) Trigemino

Muscolatura vasale

Emicrania, depressione

Vasculopatia

Vasocostrizione

5-HT1E Gi/cAMP↓ Caudato, putamen, amigdala

____ _____

5-HT1F Gi/cAMP↓ (****) Emicrania _____

Principali recettori 5-HT

Nome Effettore Distribuzione Patologia Funzione

5-HT2A Gq/G11

PLC,Ca2+↑

(*****) m. vasale e gastrointestinale, piastrine

ipertensione, alterazione mot G.I.

Aggregazionecontrazione

5-HT2B Gq/G11

PLC,Ca2+↑

m. ileale, stomaco, utero, vasi,

endotelio

_____ Contrazione

5-HT2C Gq/G11

PLC,Ca2+↑

(*******) plessi coroidei, ipotalamo, endotelio

Emicrania, _____

5-HT3 Canale ionico

Striato, corteccia, Sostanza Nigra., gangli simp.

neuroni sens.

vomito _____

Principali recettori 5-HTNome Effettore Distribuzione Patologia Funzione

5-HT4 Gs/cAMP↑ (*******) plesso mienterico,

m. G.I.

Disordini G.I. Propulsione Intestinale

5-HT7 Gs/cAMP↑ (*********) ippocampo,

m. vasale

ipertensione _____

5-HT6 Gs/cAMP↑ (********) ippocampo, accumbens

Psicosi (?) _____

5-HT5A Gs/cAMP↑ Ippocampo, cort,cervelletto,

midollo spinale

____ _____

5-HT5B _______ Ippocampo, cort,cervelletto, midollo spinale

_______ _______

Legenda tabelle(*) solo molecole di interesse terapeutico; (**)patologia; (***5-HT1D)Striato,

Accumbens, Rafe, nuclei base, ganglio trigemino, m. vasale; (****5-HT1F) Corteccia, talamo, bulbo olfattorio, midollo spinale, utero, mesenteri; (*****5-HT2A) Corteccia, ippocampo, bulbo olfattorio, midollo spinale, s. gastrointestinale, m. vasale e bronchiale, endotelio, piastrine; (******5-HT2C) Plessi coroidei, ponte, striato, ippocampo, ipotalamo, endotelio, m. spinale; (*******5-HT4) Striato, talamo, ippocampo, bulbo olfattorio, plesso mienterico, m. esofagea e vasale; (********5-HT6)Caudato, putamen, accumbens, corteccia, ippocampo, ganglio cervicale superiore; (*********5-HT7) Ippocampo, ipotalamo, talamo, collicolo sup., rafe, gangli simpatici, m. vasale e intestinale

S.N= S. Nigra, TSSA= terminali nervosi s. autonomo, Aggres =aggresssività, dep=depressione, almG.I. =alterata motilità gastrointestinale, neuroni sens.= neuroni sensitivi

Class and examples

Site Action Potential

therapeutic areas 5HT1p agonists

 Buspirone Sumitriptam

Inhibitory gastric motor neurones

Fundal relaxation Functional dyspepsia

5HT3

antagonistsOndansetronGranisetron     AlosetronCilansetron

Vagal afferentsEnteric interneurones  & secreto-motor neuronesMesenteric afferents

Inhibit nausea due to  5HT release; Inhibit opiate induced nausea; Inhibit sprial evoked responses to intestinal distension

Chemotherapy induced nauseaPost operative nauseaVisceral hypersensitivity  in IBS

5HT4 agonists

 Prucalopride

Cholinergic colonic  motor nerves (enhances  acetylcholine release)

Stimulates peristalsisAccelerates colonic transit Constipation

5HT4 partial

agonist Tegaserod

Primary afferent enteric neuronesEnterocytesExtrinsic mesenteric afferents

Stimulates peristalsisStimulates chloride secretionInhibits afferent firing in response to   distension

Constipated IBS

Combined 5HT4 agonist

and 5HT3 antagonist

    Cisapride

Motor neurones Increase oesphageal peristalsis; lower oesphagealsphineter pressure Accelerating gastric emptying and small bowel transit

Impaired oesphageal peristalsisGastroparesis Chronic intestinal pseudo-

Spiller R - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Spiller R- British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Serotonergic modulating drugs for functional gastrointestinal diseases Schematic illustration of selected neuronal and cellular sites where 5HT

receptor modulators can act as discussed in the text. 5HT acting via 5HT1p

receptors on the gastric inhibitory neurone causes the release of NO

which relaxes the gastric fundus. 5HT3 antagonists inhibit splanchnic

afferent nerve response to painful distension and inhibit vagal responses

to chemotherapy induced 5HT release. They also inhibit discharge of

secreto-motor nerves, which act via VIP, and NO. 5HT4 agonists induce

peristaltic contractions by stimulating IPAN. These activate ascending

excitatory pathways, mediated via acetylcholine and substance P,

together with descending inhibitory pathways, mediated via NO and VIP

release. Abbreviations: IPAN=intrinsic primary afferent neurone,

VIP=Vasoactive intestinal peptide, SP=substance P, NO=nitric oxide.

Microvilli

Granuli secretori

Membrana basolaterale

Spiller, Robin - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Cellule enterocromaffini (EC) della mucosa rettale

Spiller R - British Journal of Clinical Pharmacology  54 (1), 11-20, 2002

Regolazione della secrezione di 5-HT nelle ECs

Goodman&Gilman’s

Farmaci e sistema serotoninergico:

• Recettori 5-HT3: antagonisti come

l’ondansetron, il tropisetron, il dolasetron

ed il granisetron sono usati come

antiemetici nella nausea ed il vomito

indotto da farmaci antiblastici

Questi farmaci verranno trattati successivamente

Alosetron

2,3,4,5-tetraidro-5-metil-2-[(5-metil-1-H-imidazol-4-yl)metil]-1-H-pirido(4,3-b)indol-1-one,idrocloruro

A Randomized Controlled Clinical Trial of the Serotonin Type 3 Receptor Antagonist Alosetron in Women With

Diarrhea-Predominant Irritable Bowel Syndrome • IRRITABLE BOWEL syndrome (IBS) is one of the most common

functional gastrointestinal disorders seen in primary care and gastroenterology practices. Irritable bowel syndrome primarily affects women, with prevalence estimates of 14% to 24% of women in the United States and Great Britain. It negatively affects patients' daily activities and quality of life and contributes to significant increases in health care resource utilization …

• The serotonin type 3 (5-HT3) receptor antagonists represent valuable therapeutic compounds for the treatment of IBS. The 5-HT3 receptors have been identified on sensory neurons of the gut and mediate reflexes that control gastrointestinal motility and secretion, bowel function, and perception of pain. In patients with IBS, 5-HT3 receptor antagonists increase colonic compliance, slow colonic transit, and improve stool consistency

Camilleri et al., Arch Intern Med 161 (2001), pp. 1733–1740.

Tegaserod

3-(5-methossi-1H-indol-3-ilmetilene)-N-pentilcarbazimidamide maleato

TegaserodIn the past, treatment decisions were often based on the patient's

individual symptoms because there was no single drug that was

effective in relieving abdominal pain, bloating and constipation

associated with irritable bowel syndrome. However, there is growing

evidence that serotonin (5-HT), via its subtype 4 (5-HT4) receptors,

plays a pivotal role in the maintenance of overall gastrointestinal

motor function. The advent of innovative 5-HT4 receptor agonists has

demonstrated that 5-HT4 receptor stimulation can trigger the

peristaltic reflex in both animal and human gastrointestinal tract.

Effect of tegaserod

versus placebo in patients

with irritable bowel

syndrome. Müller-Lissner et al., Aliment Pharmacol Ther 15 (2001), pp. 1655–1666

Meguid MM et al., Nutrition 16:843-57, 2000

Serotonina e controllo dell’appetito