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Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission

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Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission Ch.P. 11 Ming-Kuan HU 1 School of Pharmacy Drug covered in this chapter (I) Drugs for the treatment Drugs for obesity (5- of migraine (5-HT1D/1F HT2c agonists) agonists) Lorcaserin Almotriptan Antiemetic drugs (5-HT3 Frovatriptan antagonists) Eletriptan Alosetron Naratriptan Dolasetron Rizatriptan Granisetron Sumatriptan Ondansetron Zolmitriptan Palonsetron Tropisetron 2 Drug covered in this chapter (II) Drugs for the treatment of Drugs for the treatment irritable bowel syndrome of neuropsychiatric (5-HT4 agonists) disorders Tegaserod Buspirone Hallucinogenic agents Clozapine Lysergic acid diethylamide Fluoxetine (LSD) Olanzapine 2,5-Dimethyl-4- Propranolol bromoamphetamine Risperidone 2,5-Dimethoxy-4- Trazedone iodoamphetamine Tranylcypromine Ziprasodone Zotepine 3 Neurophysiology Neurotransmitters In PNS: Ach, NE In CNS: Amino acid NTs: Glutamate, aspartate, GABA, glycine Biogenic amines: NE, dopamine, Epi, 5-HT, Histamine Ach Purines: adenosine, ATP Lipid soluble gas: NO Neuroactive peptides: as neuromodulators 4 Classification of receptors Class I: 1-Transmembrane proteins Enzyme associated Class 2: Transcriptional regulators Non-membrane, cytosolic protein with DNA-binding domains Class 3: Ion channels Integral membrane; subunit composition; each subunit or domain has 2 or more membrane inserts as a pore region, and 4 or more form the central pore of the channel Class 4: 7-Transmembrane proteins G protein-coupled receptors 5 Classification of receptors 6 Receptors and signaling pathways 7 1-Transmembrane proteins Intrinsically enzyme-associated proteins e.g. those with GCase Receptors for growth factors and related ligands Tyrosine kinase PDGF; EGF; IGF; FGF Cytokines GH; erythropoietin; IL-2, -3, & -6; IF Tumor necrosis TNF; low-affinity GF receptor Serine/threonine kinase TGFb; activin 8 Transcriptional regulators Intracellular hormone receptors For steroid hormones (estrogen & androgens); the glucocorticoids; Vit D; thyroxine; retinoic acid) Common characteristics Multiple functional domains- ligand-binding, DNA- binding, and transcriptional activation. Type I receptors for steroids: in cytoplasm and nucleus and form complexes with heat shock proteins or others. Type II receptors for vit D, ---: exclusively in nucleus and form heterodimers capable of binding to DNA in the absence of ligands 9 Ion channels Voltage-gated: for ions, e.g. Na+, K+, Ca2+ characteristic: open or close by change in membrane potential; membrane of one structural superfamily; target of many toxins or therapeutic agents Transmitter-gated: for ions, e.g. Na+, K+, Ca2+, Cl- Characteristic: open by interaction with transmitter Ach (nicotinic): cation (Na+, Ca2+) channel Glycine: anion (Cl-) channel - GABAA: anion (Cl ) channel Glutamate: cation (Na+, Ca2+) channel Serotonin: cation channel ATP (purinergic) cation (K+) channel Cyclic-nucleotide: cation channel 2+ IP3: Ca channel 10 Ion channels & neurotransmitter receptors Three types of channels on membrane of nerve cells Voltage-gated channels respond to changes in the membrane potential, e.g. Voltage-gated calcium / sodium channels Ligand-gated ion channels (ionotropic receptors) opened by the binding of neurotransmitters to the channels (only brief opening: a few msec to tens of msec) Metabotropic receptors: (via G protein) Neurotransmitters bind to G protein-coupled receptors and modulate voltage-gated channels. e.g. b-adrenoceptor: ACase activation and cAMP release (channel open can last tens of sec to min.) 11 Voltage-gated channels 12 Ligand-gated channels Ca2+ voltage- gated ion channel activated by IP3 13 7-Transmembrane proteins G protein-coupled receptors Ligands include: light-sensitive comp‟ds, odor, pheromones, hormones, NTs, e.g. Ach (muscarinic) NE (b1, b1/2, b2, a1, a2) Angiotensin (AT1) Dopamine (D2) Serotonin (5-HTD1) Histamine (H2) Opioid (m) Two principal signal transduction pathways involving the G-protein coupled receptors cAMP signal pathway Phosphatidylinositol signal pathway 14 Ligand-gated ion channels (Ionotropic receptors) Excitatory channels conducting positively charged ions: Ach 5-HT Glutamate: major excitatory NT in CNS Inhibitory channels conducting chloride ion (Cl-): GABA: major inhibitory NT in CNS Glycine: major inhibitory NT in the spinal cord 15 CNS neurotransmitters Amino acids Neutral amino acids: Glycine, GABA - Inhibitory NT; increase membrane permeability to Cl , mimicking IPSP. Acidic amino acid: Glutamate HOOC COOH Excitatory NT . ionotropic (iGlu) receptors H2N . metabotropic (mGlu) receptors. Acetylcholine (ACh) Serotonin (5-HT, 5-Hydroxytryptamine) NH2 Norepinephrine (NE) HO Dopamine (DA) Histamine N H Peptides 16 Structures of serotonin and hallucinogens The “baby boomer” of NTs Serotonin was associated with anxiety, depression, schizophrenia, drug abuse, sleep, dreaming, hallucinogenic activity, headache, appetite control, ----- “almost involved in everything”. NH2 HO N H 17 Biosynthesis and catabolism of serotonin 5-OH-tryptophol + 5-OH-indole-3-acetic acid MAO CO H HO 2 5-HT N-acetyl- N L-Trp 5-HTP 5-HT transferase H N-Ac-5-HT Melatonin Tryptophan Aromatic amino H H hydroxylase acid decarboxylase N Ac N Ac HO CH3O N N H H 5-Hydroxyindole-O- 18 methyltransferase Guanine nucleotide-binding protein (G protein) complexes Figure 3. Heterotrimeric G protein complexes are made of an alpha, beta and gamma subunit that together associate with a 7-transmembrane 19 spanning receptor protein. Serotonin receptors Figure 4. The 5-HT1A receptor couples to Gi/o. Activated Gi leads to an inhibition of adenylate cyclase via the ai subunit and opening of potassium channels via the 20 “bg subunit. Activated Go leads to a closing of calcium channels via the ao subunit. Serotonin receptors Figure 5. The 5-HT2 receptor is coupled to Gq. Upon activation, Gq induces phospholipase C to hydrolyze PIP2 to IP3 and DAG. 21 Serotonin receptors (summary) AC(+) AC(-) Receptor subtypes represented by shaded boxes and lower case designate receptors that have not been demonstrated to definitively function in native systems. Abbreviations: 3‟,5‟-cyclic adenosine IP monophosphate (cAMP); 3 phospholipase C (PLC); DAG negative (-ve); positive (+ve). 22 Schematic of processes associated with serotonergic neurotransmission 23 Serotonin receptors families Family Type Mechanism Potential 5-HT1 Gi/Go-protein cupld. Decreasing cAMP Inhibitory 5-HT2 Gq/G11-protein cupld. Increasing IP3 and DAG Excitatory + + 5-HT3 Lg-gt Na and K chnl Deplar plma memb Excitatory 5-HT4 Gs-protein cupld. Increasing cAMP Excitatory 5-HT5 Gi/Go-protein cupld. Decreasing cAMP Inhibitory 5-HT6 Gs-protein cupld. Increasing cAMP Excitatory 5-HT7 Gs-protein cupld. Increasing cAMP Excitatory 24 5-HT1A receptors Involved in sleep, impulsivity, alcoholism, sexual behavior, appetite control etc. Main focus of drug development on 5-HT1A receptors: Treatment of anxiety & depression 25 Buspirone (Buspar) Treat mixed anxious-depressive cases Antianxiety actions: (partial) agonist st 1 arylpiperazine approved as an anxiolytic actions: at presynaptic somatodendritic 5-HT1A receptors Antidepressant actions at postsynaptic 5-HT1A receptors O N N N N N . O HCl Busiprone 26 5-HT1A receptor agonists - Arylpiperazines Metabolite: 1-PP O O N N N N N N N N N N O O Buspirone Gepirone O N N N N N H N S N N N O O Ipsapirone 1-(phenyl)piperazine 5-HT1A agonists-arylpiperazines 27 Novel 5-HT1A receptor agonist Flibanserin (Addyi) 女性威而鋼 for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD), Low libido in women by Sprout Pharm approved in 2015. 28 5-HT1D receptors Involved in anxiety, depression & cerebral blood vessels, neurological inflammation. Agonists as anti-migraine agents: Sumatriptan: 5-HT1D & 5-HT1B agonist. 5-HT1B receptor may be involved in vasoconstriction. 29 5-HT1D receptor agonists N N CH NH O 3 S O O N NH N H O H Sumatriptan Zolmitriptan N N CH NH O 3 S N N O N N N H H Naratriptan Rizatriptan 5-HT1D agonists 30 5-HT1F receptors Coupled to inhibition of ACase. Possible role in contraction of neural and vascular blood vessels. Clinical significance is not known. The binding of sumatriptan to this receptor antimigraine activity 31 治療偏頭痛（migraine）之 下列有關神經傳遞物質之敘 藥物Sumatriptan是作用於 述，何者錯誤？(103-1 理) 下列何種受體？(104-2 理) A. Dopamine之前驅物是 Tyrosine A. 5-HT1A B. GABA之前驅物是 B. 5-HT 1D Glutamate C. 5-HT1E C. Norepinephrine之前驅物 D. 5-HT1F 是Tyrosine D. Serotonin之前驅物是 Tyrosine 32 5-HT2A receptor This receptor is expressed in regions of the brain believed to be involved in cognitive processes such as the prefrontal cortex, specifically in pyramidal neurons and interneurons. It is primarily coupled to Gq and activates various isoforms of phospholipase C (PLC) Receptor activation is necessary for the mechanism of action of hallucinogens. Mediate contractile responses in vascular smooth muscle Receptor activation stimulated release of ACTH, corticosterone, oxytocin, renin, & prolactin. Receptor agonists mediate certain behavioral syndromes, e.g. head twisting, wetdog shakes, back muscle contractions. [e.g. DOM ((-)-2,5-dimethoxy-4-methaphetamine)] 33 5-HT2A antagonists O O N F N N O O N F N O N H N CH3 Ketanserin Risperidone N-alkylpiperidines H H N S N CH3 Cl N N N N N N Olanzapine CH3 Clozapine CH3 34 5-HT2A antagonists Clinic use of 5-HT2A antagonists Ketanserin block 5-HT2 receptors
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