Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Axon guidance wikipedia , lookup
Synaptogenesis wikipedia , lookup
Long-term depression wikipedia , lookup
Neurotransmitter wikipedia , lookup
Spike-and-wave wikipedia , lookup
End-plate potential wikipedia , lookup
Neuromuscular junction wikipedia , lookup
NMDA receptor wikipedia , lookup
Endocannabinoid system wikipedia , lookup
Stimulus (physiology) wikipedia , lookup
Signal transduction wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Charles University in Prague, Third Faculty of Medicine Cycle II, Subject: General Pharmacology Lecture: 31th October 2012 8:00-9:30 Burian Hall, Ruská 87, Prague MOLECULAR TARGETS FOR DRUG ACTION Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Teaching Unit No. 9: Molecular targets for drug action http://vyuka.lf3.cuni.cz/ Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES Cellular basis of medicine 1. RECEPTORS J.N. Langley - one of the fathers of the chemical receptor theory 1905 Channel-linked receptors G-protein-coupled receptors Cell Membrane Cellular RECEPTORS Proteinkinase-linked receptors Intracellular - Receptors linked to gene transcription (nuclear receptors) CHANNEL-LINKED RECEPTORS („ionotropic receptors“) - about 90% of synapses in the CNS - for fast synaptic transmission (msec) - examples: NICOTINIC, NMDA RECEPTOR: Na+ flows into cells, depolarization, excitation GABAA RECEPTOR: Cl- flows into cells, hyperpolarization, inhibition CHANNEL-LINKED RECEPTORS („ionotropic receptors“) Nicotinic receptor Katzung 2-12 ale raději GABAA Katzung BG, 2001 pentameric structure - five subunits form a cluster surrounding a central transmembrane pore. When acetylcholine binds, the channel pore opens. CHANNEL-LINKED RECEPTORS („ionotropic receptors“) Cl- GABAA receptor Benzodiazep. receptor Cl- - pentameric structure - receptor for GABA, for modulatory drugs (eg. benzodiazepines) Remedia 1998 R.J. Lefkowitz & B.K. Kobilka 2012 Nobel prize G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) - sites for action of about 45% of drugs - for slow synaptic transmission (seconds - minutes) -examples: beta-adrenergic receptors, muscarinic receptors - „coupling“: RECEPTOR - serpentine receptors: a polypeptide chain traverses the membrane seven times G PROTEIN EFFECTOR G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) Katzung Fig 2-14 serpentine receptors: a polypeptide chain traverses the membrane seven times, the sites for binding ligands, G-protein Katzung BG, 2009, Fig 2-11 G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) M. Rodbell & AG Gilman 1994 Nobel prize RECEPTOR G PROTEIN - trimer, alpha, beta, gamma subunits alpha subunit: GTPase aktivity: GDPGTP, stimulation (Gs) , inhibition (GI) of the effector ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). EFFECTOR G-PROTEIN-COUPLED RECEPTORS (GPCR) („metabotropic receptors“) When a ligand binds to the GPCR it causes a conformational change in the GPCR EFFECTOR GPCR RECEPTOR G-PROTEIN Alfa Alfa GTP GDP Alfa GDPGTP Alfa betagama GDP The GPCR can then activate an associated G-protein alpha subunit by exchanging its bound GDP for a GTP eg. adenylyl cyclase Gs adenylyl cyclase in beta-adrenergic receptor Gi adenylyl cyclase in mu opioid receptor G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) RECEPTOR E.W. Sutherland Nobel Prize 1971 G-PROTEIN adenylyl cyclase cAMP 2nd messengers: ENZYM EFFECTOR fosfolipase C IP3, DAG ION CHANNEL Ca++ release Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES 2. ION CHANNELS • voltage-gated channels calcium channels - Ca++ flows into cells, calcium channel blockers sodium channels - Na++ flows into cells, blocked by local anaesthetics ligand-gated channels, G protein-gated*, and other *(directly or by intermediaries), Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES 3. CARRIER MOLECULES • „pumps“ sodium pump - Na+/K+ ATPase, „pumps“ Na+ from the cell, inhibited by cardiac glycosides proton pump - H+/K+ ATPase, „pumps“ H+ from the cell , proton pump inhibitors • transporters transporters for noradrenaline, serotonine inhibited by most antidepressants (RUI, TCA, SSRI etc) Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES 4. ENZYMES sites of action of about 30% of drugs Drugs inhibiting the enzyme: Cholinesterase Cholinesterase Inhibitors Non-Steroid Antiinflammatory Drugs Monoamine oxidase IMAO Cyclo-oxygenase Angiotensinconverting enzyme ACE Inhibitors HMG-CoA reduktase Statins and other - e.g. recently phosphodiesterase sildenafil (VIAGRA) degradating cGMP neuroamidase oseltamivir (TAMIFLU) stops the virus from chemically cutting ties with its host cell Renin-Angiotensin-Systém (RAS) system that regulates blood pressure and water (fluid) balance angiotensinogen aliskiren renin Angiotensin I causes blood vessels to constrict, ACEI angiotensin converting enzyme Angiotensin II Sartans AT1 receptors aldosteron increases the reabsorption of sodium and water in the kidney Molecular mechanisms of drug effects - summary FOUR MAJOR TARGETS FOR DRUGS: Examples of drugs:: Channel-linked receptors perif. muscle relaxants membr. about 45% of drugs,e.g. G-protein coupled receptors beta-blockers 1. RECEPTORS intracelul. Proteinkinase-linked receptors c. - Calcium chan. Voltage gated - Sodium chan. 2. ION CHANNELS imatinib Calcium ch. blockers lok. anaesthetetics Ligand-gated, G-prot.,… „pumps“ 3. CARRIER MOLECULES - sodium cardiac glykosides - proton PP inhibitors transporters 4. ENZYMES ACE, MAO, COX, HMG-CoA reductase antidepressants ACE inhibitors, IMAO Teaching Unit No. (PVJ) http://vyuka.lf3.cuni.cz PRACTICALS 10 Drugs acting via dopamine, serotonin, histamine 16 Drugs acting via ion channels and transporters Week 5 8 18 Drugs acting via enzymes 9 22 Drugs acting via nitric oxide, peptides . 11 30 Overview of molecular mechanisms of drug effects 15 TARGETS FOR BIOLOGICAL TREATMENT receptors … antibodies e.g. blocking glycoprotein GPIIb/IIIa receptors on platelets: inhibits platelets aggregation – abciximab (in percutaneous coronary intervention) monoclonal antibodies: blocking tumour necrosis factor TNFalfa from binding to TNF receptors – infliximab (in rheumat.arthritis, psoriasis, Crohn¨s disease) blocking HER 2 („Human Epidermal growth factor Receptor 2„) receptor – trastuzumab (in breast cancers)