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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
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