Advanced Receptor Psychopharmacology

Transcription

1 Advanced Receptor Psychopharmacology Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD February 2017 Lundbeck, LLC. MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

2 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. 2 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

3 Table of Contents Receptor Types and Subtypes Ionotropic vs Metabotropic Autoreceptor vs Heteroreceptor Intrinsic Activity and Functional Selectivity Neurotrophic Factors Synaptic Plasticity 3

4 Receptor Types: Ionotropic vs Metabotropic Ionotropic receptor Fast and direct action 1,2 Examples include some glutamate receptors (AMPA, NMDA, Kainate) and nicotinic acetylcholine receptors 3,4 AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; Turk E, et al. Hum Brain Mapp. 2016;37(5): Vignes M, et al. Nature. 1997;388(6638): Sargent PB. Annu Rev Neurosci. 1993;16: Image from: Purves D, et al;

5 Receptor Types: Ionotropic vs Metabotropic (continued) Metabotropic receptor Comparatively slow and indirect action 1 Examples include some Glutamate receptors (mglur) and muscarinic acetylcholine receptors 2 mglurs, metabotropic glutamate receptors. 1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3 rd edition. Sinauer Associates; Sherman SM. Trends Neurosci. 2001;24(2): Image from: Purves D, et al

6 Receptor Types: Auto vs Hetero Autoreceptor Receptor is only sensitive to the neurotransmitter of the cell type it s located on 1 Example: A serotonin (5-HT) receptor can be located on a presynaptic 5-HT neuron 2 Result: 5-HT binding to an autoreceptor on its own neuron can influence the activity or concentration of 5-HT release 3 Heteroreceptor Receptor is only sensitive to neurotransmitters of cell types other than the type it s located on 4 Example: A 5-HT receptor can be located on a dopamine (DA) neuron 5,6 Result: 5-HT binding to a heteroreceptor on a DA neuron can influence the activity or concentration of DA release 6 1. Starke K, et al. Physiol Rev. 1989;69(3): Barnes NM, et al. Neuropharmacology. 1999;38(8): Sharp T, et al. Trends Pharmacol Sci. 2007;28(12): Gilsbach R, et al. Br J Pharmacol. 2012;165(1): Esposito E, et al. Prog Brain Res. 2008;172: Bostwick JM, et al. J Clin Psychiatry. 1999;60(12):

7 Intrinsic Activity Intrinsic activity of drug at a receptor The physiologic effect a ligand elicits once bound to its receptor 1,2 Ligand can partially or fully stimulate (agonism) or inhibit (antagonism, inverse agonism) receptor activity 1,3,4 Agonist Partial agonist Antagonist Inverse agonist Full activation Partial activation No activation Reduced likelihood of activation 1. Brunton LL, Lazo, JS, Parker KL (eds). Goodman & Gilman s The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill; Jackson CM, et al. Accred Qual Assur. 2007; 2: Kore PP, et al. Open Journal of Medicinal Chemistry. 2012;2: Lieberman JA. CNS Drugs. 2004;18(4):

8 Spectrum of Intrinsic Activity Szkudlinski MW. Front Endocrinol (Lausanne). 2015;6:155. Image from: Szkudlinski MW;

9 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;

10 Neurotrophin Signaling Pathway (A) NGF BDNF NT-4/5 NT-3 (B) NGF NT-4/5 BDNF NT-3 Outside Inside TrkA receptor TrkB receptor TrkC receptor p75 receptor PI 3 kinase ras PLC SC1 NADE RhoA NGF, nerve growth factor; BDNF, brain-derived neurotrophic 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, mitogenactivated protein; IP 3, inositol trisphosphate; DAG, diacylglycerol, Ca 2+, 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; PKB Akt kinase Cell survival Kinases MAP Kinase Neurite outgrowth and neuronal differentiation IP 3 Ca 2+ release Activity dependent plasticity DAG PKC Cell cycle arrest Cell death Neurite growth 11

11 Synaptic Plasticity and Long-term Potentiation Synaptic plasticity: complex, ongoing, structural/functional alterations in the nervous system 1,2 Long-term potentiation (LTP): robust and long-lasting form of synaptic plasticity 2 Leading candidate for a cellular mechanism contributing to learning and memory 2 Glutamate receptors are required for the induction and expression of this form of plasticity, and GABA receptors are involved in their modulation 3 AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PSD, postsynaptic density Image from: Vitureira N, et al; Collingridge GL, et al. Nat Rev Neurosci. 2004;5(12): Sweatt JD. J Neurochem. 2001;76(1): Vitureira N, et al. J Cell Biol. 2013;203(2):

12 Summary Specific subtypes of neurotransmitters can have different signaling pathways (eg, ionotropic vs. metabotropic) or functions (eg, autoreceptor vs heteroreceptor), depending on their neuroanatomical location 1,2,3 Receptor activation via ligand binding can variably influence a receptor s intrinsic activity and functional selectivity 2 5 Neurotrophic factor signaling can regulate activities such as neuronal differentiation, growth, survival, and plasticity 2,6 1. Starke K, et al. Physiol Rev. 1989;69(3): Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; Gilsbach R, et al. Br J Pharmacol. 2012;165(1): Jackson CM, et al. Accred Qual Assur. 2007; 2: Gilchrist A. Trends Pharmacol Sci 2007;28(8): Lo DC. Neuron. 1995;15(5):

13 Advanced Receptor Psychopharmacology Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD February 2017 Lundbeck, LLC. MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.