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© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

Advanced Receptor Psychopharmacology

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Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

February 2017 MRC2.CORP.D.00208


This program was developed with the support of Otsuka Pharmaceutical Development &

Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or

paid contractors of Otsuka Pharmaceutical Development & Commercialization, Inc.

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© PsychU. All rights reserved.


• Receptor Types and Subtypes– Ionotropic vs Metabotropic

– Autoreceptor vs Heteroreceptor

• Intrinsic Activity and Functional Selectivity

• Neurotrophic Factors

• Synaptic Plasticity

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Table of Contents




• Ionotropic receptor– Fast and direct action1,2

– Examples include some glutamate receptors (AMPA, NMDA, Kainate) and nicotinic acetylcholine receptors3,4

4

1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

2. Turk E, et al. Hum Brain Mapp. 2016;37(5):1856-65.3. Vignes M, et al. Nature. 1997;388(6638):179-82.4. Sargent PB. Annu Rev Neurosci. 1993;16:403-43. Image from: Purves D, et al; 20041

Receptor Types: Ionotropic vs Metabotropic

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate.




• Metabotropic receptor– Comparatively slow and

indirect action1

– Examples include some Glutamate receptors (mGluR) and muscarinic acetylcholine receptors2

5

1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.2. Sherman SM. Trends Neurosci. 2001;24(2):122-6.

Image from: Purves D, et al. 20041

Receptor Types: Ionotropic vs Metabotropic (continued)

mGluRs, metabotropic glutamate receptors.



Autoreceptor

• Receptor is only sensitive to the neurotransmitter of the cell type it’s located on1

• Example:– A serotonin (5-HT) receptor can be

located on a presynaptic 5-HT neuron2

• Result:– 5-HT binding to an autoreceptor on

its own neuron can influence the activity or concentration of 5-HT release3

Heteroreceptor

• Receptor is only sensitive to neurotransmitters of cell types other than the type it’s located on4

• Example:– A 5-HT receptor can be located on

a dopamine (DA) neuron5,6

• Result:– 5-HT binding to a heteroreceptor

on a DA neuron can influence the activity or concentration of DA release6

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1. Starke K, et al. Physiol Rev. 1989;69(3):864-989.2. Barnes NM, et al. Neuropharmacology. 1999;38(8):1083-152.3. Sharp T, et al. Trends Pharmacol Sci. 2007;28(12):629-36.

Receptor Types: Auto vs Hetero

4. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.5. Esposito E, et al. Prog Brain Res. 2008;172:3-6.6. Bostwick JM, et al. J Clin Psychiatry. 1999;60(12):857-60.



1. Brunton LL, Lazo, JS, Parker KL (eds). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill; 2005.2. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.3. Kore PP, et al. Open Journal of Medicinal Chemistry. 2012;2:139-148.4. Lieberman JA. CNS Drugs. 2004;18(4):251-67.

• Intrinsic activity of drug at a receptor– The physiologic effect a ligand elicits once bound to its receptor1,2

– Ligand can partially or fully stimulate (agonism) or inhibit (antagonism, inverse agonism) receptor activity1,3,4

Intrinsic Activity

Partial activationFull activation No activation

AntagonistPartial agonistAgonist

Reduced likelihood of activation

Inverse agonist

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Spectrum of Intrinsic Activity

Szkudlinski MW. Front Endocrinol (Lausanne). 2015;6:155.

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Image from: Szkudlinski MW; 2015



Neurotrophic Factors

• Greek “trophé,” meaning “nourishment”• Regulate neuronal differentiation and growth• Signaling via neurotrophic factors can activate:

– cell survival/death– synapse stabilization/elimination– process growth/retraction

• Types:– Nerve growth factor (NGF)– Brain-derived neurotrophic factor (BDNF)– Neurotrophin 3 (NT-3)– Neurotrophin 4/5 (NT-4/5)

Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.

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Neurotrophin Signaling Pathway

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(B)

Outside

Inside

TrkB receptor

PI 3 kinase ras PLC

PKBAkt kinase

Kinases

MAP Kinase

IP3 DAG

Ca2+

release PKC

Cellsurvival

Neuriteoutgrowth

and neuronaldifferentiation

Activity–dependentplasticity

TrkC receptorTrkA receptor

(A) NGF BDNF NT-4/5 NT-3

Neuritegrowth

Cell cycle arrest

Celldeath

RhoASC1 NADE

p75 receptor

BDNF

NGF NT-4/5NT-3

NGF, nerve growth factor; BDNF, brain-derivedneurotrophic factor; NT, neurotrophin; Trk, tyrosine receptor kinase; PI 3, phosphoinositide 3; ras, rat sarcoma; PLC, phospholipase C; PKB, protein kinase B; Akt, AKT serine/threonine kinase 1; MAP, mitogen-activated protein; IP3, inositol trisphosphate; DAG, diacylglycerol, Ca2+, calcium; PKC, protein kinase C; SC1, Schwann cell 1; NADE, neurotrophin-associated cell death executor; RhoA, Ras homolog gene family member A.

Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.



AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PSD, postsynaptic density

1. Collingridge GL, et al. Nat Rev Neurosci. 2004;5(12):952-62.2. Sweatt JD. J Neurochem. 2001;76(1):1-10.3. Vitureira N, et al. J Cell Biol. 2013;203(2):175-86.

Synaptic plasticity: complex, ongoing, structural/functional alterations in the nervous system1,2

• Long-term potentiation (LTP): robust and long-lasting form of synaptic plasticity2

– Leading candidate for a cellular mechanism contributing to learning and memory2

– Glutamate receptors are required for the induction and expression of this form of plasticity, and GABA receptors are involved in their modulation3

Synaptic Plasticity and Long-term Potentiation

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Image from: Vitureira N, et al; 20133



• Specific subtypes of neurotransmitters can have different signaling pathways (eg, ionotropic vs. metabotropic) or functions (eg, autoreceptor vs heteroreceptor), depending on their neuroanatomical location1,2,3

• Receptor activation via ligand binding can variably influence a receptor’s intrinsic activity and functional selectivity2–5

• Neurotrophic factor signaling can regulate activities such as neuronal differentiation, growth, survival, and plasticity2,6

Summary

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1. Starke K, et al. Physiol Rev. 1989;69(3):864-989.2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.3. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.4. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.5. Gilchrist A. Trends Pharmacol Sci 2007;28(8):431-437.6. Lo DC. Neuron. 1995;15(5):979-81.


© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

Advanced Receptor Psychopharmacology

14

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

February 2017 MRC2.CORP.D.00208

advanced receptor psychopharmacology...advanced receptor psychopharmacology. 1. otsuka...

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