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Home , Alosetron, Flibanserin, Prucalopride, Ramosetron, Tegaserod, Tropisetron

Receptors and Drugs Affecting 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)  drugs (5-HT3  antagonists)   Palonsetron 

2

Drug covered in this chapter (II)

 Drugs for the treatment of  Drugs for the treatment of neuropsychiatric (5-HT4 agonists) disorders   Hallucinogenic agents   Lysergic acid diethylamide  (LSD)   2,5-Dimethyl-4-  bromoamphetamine   2,5-Dimethoxy-4-  Trazedone iodoamphetamine  Tranylcypromine  Ziprasodone 

3 Neurophysiology

 In PNS: Ach, NE  In CNS:

 Amino acid NTs: Glutamate, aspartate, GABA,

 Biogenic amines: NE, , 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  kinase

 PDGF; EGF; IGF; FGF  Cytokines

 GH; erythropoietin; IL-2, -3, & -6; IF  Tumor necrosis

 TNF; low-affinity GF / kinase

 TGFb; activin

8

Transcriptional regulators

 Intracellular receptors  For steroid ( & ); the glucocorticoids; Vit D; thyroxine; retinoic acid)  Common characteristics  Multiple functional domains- -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 & 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)  (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.  (ACh)  Serotonin (5-HT, 5-Hydroxytryptamine) NH2  (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, , 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 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 on 5-HT1A receptors: Treatment of anxiety & depression

25 Buspirone (Buspar)

 Treat mixed anxious-depressive cases  Antianxiety actions: (partial) st  1 arylpiperazine approved as an anxiolytic

 actions: at presynaptic somatodendritic 5-HT1A receptors  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 O N N N N N H N S N N N O O 1-(phenyl)

5-HT1A agonists-arylpiperazines

27 Novel 5-HT1A receptor agonist

(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 of hallucinogens.  Mediate contractile responses in vascular smooth muscle  Receptor activation stimulated release of ACTH, corticosterone, , 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 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 on platelet; antagonizes platelet aggregation.

 block a1 adrenoceptors: treatment of hypertension.   Reduce thromboxane formation  Never marketed, only used in scientific research.

35 5-HT2C receptor

 Lorcaserin (Belviq, by Arena Pharm.)  a prescription weight-loss drug approved by FDA June, 2012

 Use for pts with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who have CVD

 induces satiety thru the activation of 5-HT2C receptor, found only in the brain.

 at least 35% of treated subjects achieve 5% weight loss after one year and that this number is double the number of responders in the placebo group.

 In individuals with diabetes, lorcaserin also improved glycemic control, regardless of whether the patients lost weight

36 5-HT3 antagonists

 Activation triggers opening of nonselective cation channels (Na+, Ca2+ influx, K+ efflux).  Clinic use: “gold standard” for the treatment of - & radiotherapy-induced and  e.g. ondansetron, granisetron, tropisetron (in EU), (a new one)

 Activation Leading to dopamine release, thus 5-HT3 receptors antagonists acts as & anxiolytics.  Antagonists can induce cognition enhancing effects.

37 5-HT3 antagonists

N NH N N O O N CH3 CH3 CH N 3 N CH N N 3 CH O O 3 O O H N CH3 N H N Alosetron N Ondansetron N N H CH3 CH3 N H N Palonosetron NH O Granisetron Tropisetron O N CH H N 3 N

CH3 CH3 Fabesetron

Imidazole-containing 5-HT3 antagonists 38 Palonosetron HCl

 Palonosetron HCl (Aloxi) 注射劑可用於預防化學療法 引起之噁心與嘔吐。對於中度致嘔性癌症化學療法， Aloxi可預防起始及反覆療程引起之急性及延遲性噁心 與嘔吐；對於重度致嘔性癌症化學療法，則可預防起 始及反覆療程引起之急性噁心與嘔吐。

39 Substance P/NK-1

: for chemotherapy-induced nausea  st  (Emend ): 1 NK1 receptor antagonist for chemotherapy-induced emesis

Aprepitant

40 5-HT4 receptors and agents

 A Gs protein-coupled receptors ( activating cAMP)  In CNS: slow excitatory response to 5-HT  Agonists may restore deficits in cognitive function  Antagonists may be useful as anxiolytics  In PNS: facilitate Ach release use as . Treating irritable bowel syndrome (IBS) . being withdrawn due to fatal cardiac arrhythmia . Lengthening the period of ventricular repolarization by reducing the slowly activating K-repolarization current . causing sudden death with prolongation of the corrected QT (QTc)

: also a 5-HT4 agonist as a prokinetic agent

MeO O F N N O H H2N Cl Cisapride 41 Irritable bowel syndrome (IBS, 激躁性大腸徵候群)

 Characterized by abdominal discomfort with altered bowel function (i.e. [IBS-C], [IBS-D], alternating constipation and diarrhea [IBS-A]).

 5-HT3 receptors: excitation of GI  increased motility, secretion, & excitation

 5-HT4 receptors: GI motility  Drugs for IBS in clinic

 Alosetron: a 5-HT3 antagonist  tend to be constipation ®  Tegaserod (Zelnorm ): a 5-HT4 agonist  accelerate small bowel and colonic transit (but, withdrawal from market in 2007)

 Due to an increase of ischemic events, e.g. angina & stroke. NH N CH MeO N N 3 H H N H an aminoguanidine indole 42 Tegaserod New drug for Irritable bowel syndrome

: m-opioid receptor agonist and d-opioid receptor antagonist, approved in 2015.  acts locally in the , possibly decreasing adverse effects on the CNS.

43 5-HT5 receptors and agents

 Pharmacological functions unknown

 Identified as 5-HT5A and 5-HT5B receptors  May coupled to ACase and also open K+ channel

after IP3 formation

 5-HT5A involved in regulating astrocyte physiology with relevance to gliosis膠質細胞增生; schizophrenia.

 No 5-HT5A-selective agonists or antagonists reported

44 5-HT6 receptors and agents

 A Gs protein-coupled receptor in CNS  Certain atypical agents and

bind to 5-HT6 with Ki in the nM range  i.e. (as agonist)  , clozapine, and methithepin act as antagonists

45 5-HT7 receptors and agents

 A Gs protein-coupled receptor in CNS

 3 subtypes in human: 5-HT7a, 5-HT7b, 5-HT7d.

 5-HT7 antagonists  SB-258719 (Ki ~ 30 nM); SB-269970 (Ki = 1.3 nM)

 5-HT7 agonists  N-arylaminoimidazolines  Clinic implications  Regulating circadian rhythm for jet lag or sleep disorders  Relaxing coronary artery for Coronary heart disease

46 Serotonin transporter (SERT)

 Structure  12-transmembrane protein (TM12)  Both N- & C-terminal located intracellular side  50% homology with NET and DT  SERT blockers: treatment of depression, obsessive- compulsive panic disorders (OCPDs)  antidepressants (TCAs): block SERT and NET  SSRIs: selectively block SERT: i.e. fluoxetine

 Some SSRIs and TCAs also bind to 5-HT2 as antagonist, i.e. .

 Trazodone also as 5-HT2C agonist (metabolite: mCPP inducing panic attack and increasing OCPD)

47 Fluoxetine (Prozac)

 Prozac is the most activating, longest-lasting and least selective. The mood-brightening, resilience- enhancing and anti-anxiety properties of the SSRIs really can make a (very) modest percentage of the population feel "better than well".

O NHCH F3C 3

Fluoxetine (Prozac)

48 Trazodone (Desyrel)

 5-HT2A receptor antagonist  active metabolite: mCPP  responsible for some of its side-effects, such as and migraines  Side effects: penis erectile, priapsm(異常勃起)

Cl O N N N N N Trazodone

49 St John„s wort (聖約翰草,貫葉連翹)

 St John„s wort is important for a different reason altogether. Many constitutionally unhappy people refuse to have anything to do with orthodox western medicine. They won't take "unnatural" pharmaceutical products at all. In consequence, they spend much of their lives trapped in a squalid psychochemical ghetto of chronic low spirits. The only sort of remedy that they'll conceivably contemplate taking must carry a "natural" label and soothingly "herbal" description. It cannonballed onto the American self-help scene after being hailed as "nature's Prozac."

Hypericum (Hypericin金絲桃素) 50  下列何種神經傳遞物的  下列胺基酸中，何者是 化學結構與melatonin最 serotonin 生合成的原料？ 類似？ (98-2) (97-1) (A) Acetylcholine  (A) L- (B) Dopamine  (B) L-Tyrosine (C) Norepinephrine  (C) D-Tyrosine (D) 5-HT  (D) L-Tryptophan

51  Tegaserod在臨床上可用於緩  下列有關trazodone之敘述，何 解irritable bowel syndrome， 者正確？(104-1) 其主要是作用在那一個受體  A. 作用機轉為5-HT2 agonist 上？ (101-1)  B. 其結構與fluoxetine類似  A Muscarinic M 受體 1  C. 具有triazolopyridine之結構  B Histamine H 受體 2  D. 代謝為不具活性之m-  C Dopamine D2受體 chlorophenylpiperazine

 D Serotonin 5-HT4受體

52 Subtypes of mammalian serotonin receptors

53 Summary for serotonergic system

 Steps involved in the synthesis and release of serotonin  The distribution of some 5-HT receptors on different components of the serotonergic synapse

54 Norepinephrine

 Steps involved in the synthesis and release of norepinephrine  synthesis of norepinephrine takes place in the storage vesicles

55 Epinephrine

 Steps involved in the synthesis and release of epinephrine  norepinephrine stored in the vesicles leaks out into the cytoplasm and is converted into epinephrine by the enzyme phenylethanolamine -N-methyl- transferase (PNMT)

56 Acetylcholine

 Steps involved in the synthesis and release of acetylcholine

57 Glutamate

58 GABA

59 Dopamine

60