Basic Principles of Neuropharmacology PDF

Basic Principles of Neuropharmacology 10 defineligandsandtheconceptofbinding introduceandexplaindiff typesof agonists andexplain diff typesof agonistsand antagonists andtheirinteraction understandandexplain concentration response relationships defineaffinityand...

Basic Principles of Neuropharmacology 10 defineligandsandtheconceptofbinding introduceandexplaindiff typesof agonists andexplain diff typesof agonistsand antagonists andtheirinteraction understandandexplain concentration response relationships defineaffinityand efficacy and potency discuss sparereceptorsandtheirrolefor ligand efficacy discuss selectivity Binding of ligands to receptors ligand anychemicalthat bindsto orcombines with a receptor receptor cellular macromolecule or assembly of macromolecules concerneddirectlyandspecifically in chemical signallybetweenandwithincells Binding anactiveprocess of ligandsbinding to receptors whichhappensduetoalignment of 3D shapes andbiophysicalproperties forces betweentheligandandbindingsite onthereceptor multiplepointsofinteractionmaybeneeded within abindingsiteforbindingtooccur hydrophilicandhydrophobicchargesites van der waal electrostatic covalent Bindinghappens with a force facilitatef indind of onepartof the molecule can ou prevent the bindingof anotherpart through shape change Ligands their binding to receptors endogenousligands ligandsproducednaturally by the body e g neurotransmittersandother molecules that can bind to receptors exogenous ligands endogenousligandscanbesynthesised in the lab ormodifiedtochangetheir properties the conceptof binding ofligandsto theirreceptors intissues was developed in 1960susingradio ligand bindingassays to quantifytheamountofligandboundto receptors aligand neurotransmitter radiolabelled andincubatedwith atissuepreparation whichis washed extensively to removelooselybounddrug a radioactive atomtypically 3H C or 1 mustbeaddedto theligandwithoutaltering its binding properties ligand neurochemical which binds to receptor The radio ligand binding assay tomembrane The total binding of a ligand to the tissue preparation comprises of 2 components specific binding I saturable non specific binding non saturable give off inaccurate signals washinghelps remove some non specific ligands binded to membrane but some remain because of force of binding specific non specific binding Totalbinding total amountbeing observed Nonspecificbinding nonsaturable portion of bindingthat's not associated with the specific binding siteunderinvestigation specificbinding calculated as the differencebetweentotaland non specific bindingandreflects the amountof radioligandbound to the specificbindingsite  Quantification of radioligand binding if there were 100ligands and 100receptors not all will bind to the receptorsbecauseof the force ofbindingtheycouldbeboundto a non specificbinding site nonsaturable 109 the concentrations to easily determine50 linear Kd concentration of ligand at which half of the maximal binding sites Bmax are occupied The specificbinding of a ligand to a tissue preparation when the ligand is at is equilibriumwith the receptors quantifiedaccording to 2 properties theaffinityof thebindingwhich is expressed as a dissociation constant Kd totalamountofbinding Bmax if no compounds we get more non specific bindingnot specificbinding in a perfect word inhibition of 50 of the binding sites corresponds to inhibition of 50 of receptors i e 50 of receptor occupancy Autoradiography I tissue is incubated with a radiolabelled ligand to allow it to bind to itstargets 2 tissue is thenexposed tophoto film 3 radiation emittedby the radioactive ligandexposes the film and creates a picture highlighting the specificpattern of binding in the brain to produce specific images scientists calculated the amount of compounds needed to minimise non specific binding d Binding studies describe the physical relationship between a drug and its target but do not directly asses the physiological or functional consequences of this association What is biologicalresponse or effect ligands described asagonistsandantagonists full agonist geee a ligands agonists orantagonists described intermsofeffectsandtheirability partial agonist to bindto theirtargets agonists produceeffects in biologicaltissue ÉÉE antagonist inert they can be full partial or inverse antagonists do nothaveeffectsof their own on paraginyerse biological tissue butcan blockeffects evoked by agonists antagonists effectis to antagonise theactionof agoniststheycan be ÉtEÉv fullingsnist competitive or noncompetitive sonot being ableto contractmuscle isn'tbecause agonistdidn'tproduceeffectbutthe antagonist blocked the agonist Quantification of an agonist effect usually abiologicalresponse invitroor invivo which is elicitedby an agonist that is measured using a graphplottedas concentration responsive curve invitro or dose response curve in vivo Linearplot agonist effect concentration response curvesallow us to estimate the maximalresponse that the drug can produce E max and the effective concentration ECso or dose EDso needed to produce a 50 maximal response logarithmicplotpreferred for visualising concentration responserelationships because it's easier to determine the potencyoftheligand ECsovaluebyplacing it onthelinearportionofthe curve the conc whichproduced 50 Of the maximum response Emax max response the drug can produce ECso effective conc needed to produce 50 Max response EDso effective dose needed to produce 50 max response comparing potency of diff agonists concentration responserelationships for 3 agoniststhat vary in potency agonists A B and Chavesame efficacy but differ in efficacy allhave same Emax A is most potentbecause it hasthelowest ECso Value 1 SMM concentration response relationships for 3 agoniststhatvaryinefficacy eachagonisthas the same E so equipotent but differinterms of maxresponsetheyproduce agonist A has a relative efficacy two times greaterthan agonist B partial agonist if aknownagonistproduces full effect on site anyother agonistthatcanproduce fulleffect is a partial agonist Partial v s full agonist Whenpartialagonistbindsto receptor it will elicit only a smallresponse because itlacks a portionofthemolecule required for the fullphysiologicaleffect or it binds to a slightlydifferentsite onthe receptor BUT a partialagonistwhilebeinglesseffective can be more potentthen a full agonist Herethepartialagonisthas a higherpotency than the full agonist because ECso of full agonist is Emax of partialagonist inthe presence of a full agonist a partial agonist will act as a functionalantagonist competingwiththe fullagonistfor thesame receptor thisreducestheabilityof the full agonist to producetheMax effect Maximal drug responses spare receptors Repeated application of agonists can lead to ve leptor desensitisation or tolerance thatmay be overcome by increasingdose why Linear relationship maximal response when all receptors are occupied Hyperbolic relationship in most mammaliansystems relationship between receptor occupancy and drug response is hyperbolic there's a range ofdrugswherereceptors maximal responses at less than are octupied to an extent wherethe maximal receptor occupancy maximum biologicaleffectis produced and activation bindingof other some receptors are spave receptors won't enhance effect ability to concof drugs relate SFTPreceptorswhenefficac drogst to ability of activating spare Whydo we need spare receptors To amplify efficacy  other types of conc response curves An inverted U shaped curve indicates that the biologicalresponse elicitedbyanagonist progressively increases as the agonistconc and subsequentlypeaks at a moderate conc higher conc elicitprogressively smallerresponses many drugs follow this U shaped curve this is why max doseneeds to be established so unwanted side effects canbe avoided competitive antagonists competitiveantagonistcompetes withan agonist or endogenousligand for the same binding site on the receptor the antagonist doesn't alter the efficacyofthe agonistbecausethesame no receptors areavailable to bothdrugs antagonistblockingreceptor noeffectof agonist concentration ofthe agonist will overcomethe effectof a competitive antagonist  watch lecture 39min for example Noncompetitive antagonist noncompetitive antagonist works at completely diff binding siteandsattersthe configuration of thereceptor for the agoni it reduces the numberof receptors for the agonist to bind to the potency remains the same but efficacy is greatly reduced by addingmore agonists we can't overcome this if there are many spare releptors this could be overcome How do inert antagonists produce behavioural responses By preventing theagonist action preventing biological effect competitiveantagonists compete with agonists or endogenous ligands for the same binding site on the receptor noncompetitive antagonistsbindto an allosteric non agonist site onthe receptor to prevent activation of the receptor canbepositive ornegative but negative allosteric sites are most common Types of receptor antagonists 1 competitive non competitive 1 irreversible functional pseudo irreversible allosteric acts assecond simple chemically receptor competitive slowly dissociating modifiesreceptor In the presence of a constant conc of an agonist endogenous or exogenous andby systematically changing the antagonistconcwe can quantify the inhibitory effect of the antagonist action on the agonistinducedresponse The Cso value half maximal inhibitoryconclindicates how much antagonist is needed to inhibit a biologicalprocess by half 1150valuecanbeused to compare potency of antagonists in difftissues summary agonists antagonists modulators summary affinity potency and efficacy receptorbindingcanbe measured by radioligand Real word problems theybindtomanyother receptors