1. Molecular Targets For Drug Action (syllabus -prof.Kršiak) FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES

2. Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES

3. RECEPTORS Cell Membrane Intracellular Receptors linked to gene transcription (nuclear receptors) Channel-linked receptors G-protein-coupled receptors Kinase-linked receptors 1. RECEPTORS

4. 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 GABA A RECEPTOR: Cl - flows into cells, hyperpolarization, inhibition

5. CHANNEL-LINKED RECEPTORS („ionotropic receptors“) Katzung 2-12 ale raději GABA A Katzung BG, 2001 Nicotinic receptor pentameric structure - five subunits form a cluster surrounding a central transmembrane pore. When acetylcholine binds, the channel pore opens.

6. Remedia 1998 CHANNEL-LINKED RECEPTORS („ionotropic receptors“) GABA A receptor - pentameric structure - receptor for GABA, for modulatory drugs (eg. benzodiazepines)

7. 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, the extracellular terminal (NH 2 ), the intracelullar carboxyl terminal, sites for binding ligands, G-protein G PROTEIN EFEKTOR

8. G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) Katzung Fig 2-14 Katzung BG, 2001serpentine receptors: a polypeptide chain traverses the membrane seven times, the extracellular terminal (NH 2 ), the intracelullar carboxyl terminal, sites for binding ligands, G- protein

9. G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) RECEPTOR G PROTEIN - trimer, , ,  subunits  subunit: GDP  GTP, GTPase aktivity stimulation (G S ), inhibition (G I ) of the effector EFFECTOR

10. betagama ENZYM Alfa GDP  GTP AlfaGTP Alfa GDP ENZYM RECEPTOR G-PROTEIN Alfa GDP G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) eg. adenylyl cyclase G s  beta-adrenergic receptor G i  mu opioid receptor Alfa GDP ENZYME

11. EFFECTOR ENZYM ION CHANNEL adenylyl cyklase  cAMP fosfolipase C  IP 3, DAG Proteinkinases G-PROTEIN-COUPLED RECEPTORS („metabotropic receptors“) G-PROTEIN RECEPTOR Ca ++ release 2 nd messengers: Activation of cellular functions* *eg. contractile proteins, enzymes, transporters, ion channels

12. site-directed mutagenesis

13. Molecular Targets For Drug Action) FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES

14. 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),

15. Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES

16. 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)

17. Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES

18. sites of action of about 30% of drugs