Lecture 1 - Introduction to Neurotransmitters

- Signalling within the cell - Signalling affecting the producing cell via receptors - Signalling in immediately adjacent cells - Signalling in immediate surroundings of the cell Endocrine, distant cells, usually through circulation Define the following: - Intracrine - Autocrine - Juxtacrine - Paracrine - Cytokines --> a class of signalling proteins of a small size. mainly involved in regulating the immune system Give examples of 3 types of signalling molecules and a brief description of each - Hormones --> produced by glands, reach their targets through circulation. Chemically they can be classified as amino acids/peptides, eicosanoids, steroids - Neurotransmitters --> small organic molecules released in the synaptic cleft to allow communication between neurons. Signalling usually goes from the pre-synaptic neuron to the post-synaptic neuron. However, it is possible, for a feedback mechanism, to travel in the opposite direction (e.g. adenosine, GABA) Recap of synaptic transmission - look at slide 4 in ppt G protein-coupled receptors (GPCRs) - Large superfamily of integral membrane proteins Give some features of G protein-coupled - 7 transmembrane hydrophobic helices receptors - Traditionally organized in 6 subfamilies (A - F) External signal e.g. NT binding to extraGive a general example of how a signal cellular part --> change in structural concould move across a cellular junction formation of the protein --> signal goes inside the cell 1/5 Just as neurotransmitters are a subgroup of signalling molecules, neurotransmitters that interact with Class A GPCRs are a subgroup of neurotransmitters. Give some examples of common biogenic amines Adrenergic Transmission: - What is adrenaline? - We can develop molecules that are selective for a certain subtype to achieve tissue-specific effects. Give the common structural features that stand out when looking at the natural form of adrenaline - Adrenaline - Histamine - Serotonin - Dopamine - Acetylcholine - A neurotransmitter that stimulates the sympathetic nervous system (fight-or-flight) - Aromatic diol system - Chiral centre - Secondary amine GPCRs as drug targets - Affinity (concentration to achieve response) --> Does the drug bind to the protein? What 2 things do we need to consider - Efficacy (pharmacological effect) --> when designing drugs to target GPCRs? What happens? What is the clinical consequence of the drug and protein binding to eachother? - Both contribute to potency - Agonist --> drug and protein bind to eachother and the effect is to fully increase the response e.g. mimic the release of a large excess of adrenaline - Partial agonist --> a drug molecule that has more of an in-between effect. Binds Drugs can be designed in different ways to the receptors, increase the response to have different pharmacological efbut not as high an agonist fects. What 4 different ways could the - Antagonist --> binds to the receptor but drug be designed to act causes no pharmacological change i.e. blocks the receptor - Inverse antagonist --> binds to the receptor and causes a decrease in the effect/signal i.e. binds, has a pharmacological effect but it's the opposite 2/5 - Salbutamol ²2selective agonist (bronchodilator: treatment of asthma) Selectivity mainly attributed to tert-butyl group (Log P = +0.7) - Salmeterol Give 2 examples of adrenergic agonists Increased selectivity towards ²2 and a description of each Slow onset and extended duration Slow onset attributed to increased lipophilicity (Log P = +3.9) Consider that this is only (really!) an extension of an alkyl chain Look at structures on slide 11 in ppt - Pindolol Commercialised for treatment of high blood pressure / angina Lipophilicity / lack of catechol hydrogen bond acceptors/donors No selectivity between ²1 / ²2subtypes Give 2 examples of adrenergic antagonists and a description of each - Atenolol Next generation beta blockers are selective for ²1 Treatment of hypertension, angina, and acute MI Look at structures on slide 11 in ppt Therapeutic Opportunities What is serotonin? - A neurotransmitter that plays a role in central and peripheral nervous systems, including regulating mood, behaviour, and other physiological functions - Increasing the serotonergic tone can be beneficial for treating various conditions Look at structure on slide 14 in ppt 3/5 - Fluoxetine An example of marketed molecules that - Increases serotonergic tone by binding have an effect on serotonin are Selec- (blocking) the activity of the serotonin tive serotonin reuptake inhibitors (SS- transporter RIs). Give an example of an SSRI and - Left in the synaptic cleft (as re-uptake explain what it does is blocked) the effect of serotonin is enhanced and lasts longer Mitochondrial membrane flavin-containAnother example of therapeutic targets ing enzymes that catalyse the oxidaare Monoamine oxidases (MAOs). What tive deamination of monoamines (adrenare these? aline, serotonin, dopamine, etc.) MAO-A --> adrenaline, dopamine, serotonin There are two main isoforms. What are MAO-B --> trace amines (e.g. tyramine) they? Each one with specific substrate specificity What can Monoamine oxidases do? - In their oxidative form they can break down amines - When this molecule interacts with a MAO enzyme, degradation occurs --> breaking down the neurotransmitter - This is called oxidative deamination. It uses FAD+ as a cofactor (hydrogen acceptor), itself becoming reduced to NADH2 If Monoamine oxidases keep breaking down, for example dopamine, the our mood at particular points in time will be a lot lower. So, what can be done? Prevent the breaking down of the molecule by this pathway or potentially inhibit it = increase in mood = useful in mental health indications What have high or low levels of MAOs been associated with? Several pathological conditions including: - Depression - Schizophrenia - Addiction - Migraine 4/5 First generation MAOs are ___________ Unselective --> target type a type b Next generation selective inhibitors have been recently developed, e.g. Selegiline (this is commonly co-administered with L-DOPA for treatment of early stage Parkinson's disease) 5/5