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بسم هللا الرحمن الرحيم "وسع ربنا كل ٍ شئ علما على هللا توكلنا ربنا افتح بينناوبين قومنا بالحق وأنت خير الف اتحين" 5/1/2017األعراف اآلية 89من سورة Continuous Assessment: • • • First Assessment Test Second Assessment Test Term Activity* 20% 20% 20% Final Examination: 6. Final Paper test Final Exam 5/1/2017 40% 2 Gareth Thomas. Medicinal , An Introduction, John Wiley and sons, Ltd, 1st edition, 2000. 2. Williams, D.\a. and Lemeke, Foye’s Principle of Medicinal Chemistry , Lippincott Williams and Wilkins, Philadephia, PA., 5th edition, 2002. 3. Gareth Thomas Medicinal Chemistry, An Introduction, 2nd Edition. Wiley-Interscience (2008) 4. Graham L. Patrick, An Introduction to Medicinal Chemistry, 3ed Ed.; Oxford University Press (2005) 1. 5/1/2017 ● Medicinal chemistry is a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships (SAR). ● Drugs are strictly defined as chemical substances that are used to prevent or cure 5/1/2017 diseases in human, animals and plants. – The word drug, therefore, imposes an action-effect context within which the properties of a substance are described. For example when a drug is defined as an analgesic, it means that it is used to treat pain ….. Thus a drug may described as having analgesic, vasodepressor, anticonvulsant, antibacterial, …….…etc properties. 5/1/2017 ● Drugs activity, solubility in plasma and distribution to various tissues is dependent on their physicochemical properties. Even the interaction of a drug with a receptor or an enzyme is dependent on characteristics of a drug molecule, such as ionization, electron distribution, polarity and electronegativity. To understand drug action, the physicochemical parameters that make this action possible should be also understood. ● 5/1/2017 Drug names: (nomenclature) • Chemical – 6-Chloro-3,4-dihydro-7-sulfamoyl-2H1,2,4-benzothiadiazine 1,1-dioxide • • Trade – Hydrodiuril®, Hydroaquil®, Esidrex®, Urozide®, Novohydrazide® etc. Many others Generic – Hydrochlorothiazide 5/1/2017 Parenteral Route Target Receptor Site (Desired Biological Activity) Drug in Solution Drug in Formulation Drug in Blood Membrane Deaggregation, Dissolution Absorption across Membrane Excretion 5/1/2017 Tissue Depots Non-Target Receptor Site (Side Effects) Pharmaceutical Pharmacokinetic Pharmacodynamic Phase Phase Phase Dosage form Tablet, etc. 5/1/2017 Absorption Distribution Metabolism Excretion etc Drug action Drug-receptor Interaction Disposition of a drug after oral administration 5/1/2017 Disposition of a drug after oral administration Tissue Reservoirs Receptors D + R DR Free drug Plasma protein binding 5/1/2017 Biotransformation Liver D -> metabolite M Excretion Cell Structure • Human, animal and plant cells are eukaryotic cells • The nucleus contains the genetic blueprint for life (DNA) • The fluid contents of the cell are known as the cytoplasm • Structures within the cell are known as organelles • Mitochondria are the source of energy production • Ribosomes are the cell’s protein ‘factories’ • Rough endoplasmic reticulum is the location for protein synthesis 5/1/2017 Cell Membrane Exterior High [Na+] Proteins Phospholipid Bilayer Interior High [K+] 5/1/2017 Cell Membrane CH2CH2NMe3 Polar Head Group Polar Head Group O O P O O CH2 CH O O Hydrophobic Tails Hydrophobic Tails 5/1/2017 CH2 O O Cell Membrane CH2CH2NMe3 Polar Head Group O O P O O CH2 CH O O Hydrophobic Tails 5/1/2017 CH2 O O Cell Membrane • The cell membrane is made up of a phospholipid bilayer • The hydrophobic tails interact with each other by van der Waals interactions and are hidden from the aqueous media • The polar head groups interact with water at the inner and outer surfaces of the membrane • The cell membrane provides a hydrophobic barrier around the cell, preventing the passage of water and polar molecules • Proteins are present, floating in the cell membrane • Some act as ion channels and carrier proteins 5/1/2017 Drug Targets - Cell Membrane Lipids TUNNEL HO2C OH OH CO2H Sugar Sugar OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO Polar tunnel formed Escape route for ions CELL MEMBRANE 5/1/2017 Sugar HO2C Sugar OH OH CO2H Diagram of Cell Membrane Lipid exterior Protein Hydrophilic region Hydrophobic interior 5/1/2017 Cross-section through the cell membrane Membrane passage of drugs 5/1/2017 Mechanisms of Drug Absorption 1. Passive Diffusion The transfer of most drugs across a biological membrane occurs by passive diffusion, a natural tendency for molecules to move from higher concentration to one of lower concentration. This movement of drug molecules is caused by the kinetic energy of the molecules. It is a major route for the transfer of uncharged and non-polar solutes that readily dissolve in lipids through membranes. 5/1/2017 PASSIVE DIFFUSION = Solute molecule Lipid membrane Side A Side B 1. Driving force is a concentration or electrochemical gradient 2. At equilibrium, [drug]Side A = [drug]Side B ; no further net movement of drug 5/1/2017 2. FACILITATED or Carrier Mediated DIFFUSION It is the transport of a drug through a membrane by the action of transporter proteins. The drug combines with a specific proteins causing this protein to change its confirmation which result in the transport of the solute from one side of the membrane to the other. • Some solutes diffuse across membranes down electrochemical gradients more rapidly than expected from size, charge, and partition coefficients • “Ping-Pong” mechanism explains facilitated diffusion • Carrier protein exists in two principal conformations: – “Pong” state - exposed to high [solute], solutes bind to specific sites on carrier protein – Conformational change exposes carrier to lower [solute] “ping” state 5/1/2017 – Process is reversible, net flux depends on concentration gradient FACILITATED or Carrier Mediated DIFFUSION Lipid membrane Side A Side B C C C C C = Solute molecule C = carrier protein 1. Process involves a carrier protein, “C” 2. Driving force is a concentration or electrochemical gradient 3. Limited number of carrier proteins in membrane; i.e., a saturable process 4. At equilibrium, [drug]Side A = [drug]Side B; no further net movement of drug 5. No expenditure of energy •The requirement for carrier mediated transport is structural similarities between the drug and the substrate 5/1/2017 transported by these carriers. normally 3- ACTIVE TRANSPORT = Solute molecule Lipid membrane Side B Side A CATP PUMP 1. E required - process driven by ATPdependent pump 2. ATP-pump is used to drive a solute against its concentration or electrochemical gradient 3. Limited number of pumps in membrane; i.e., a saturable process 4. At equilibrium, [drug]Side A < [drug]Side B ADP 5/1/2017 • Active transport differs from passive diffusion in the following ways: 1. The transport of the drug occurs against a concentration gradient. 2. The transport mechanism can become saturated at high drug concentration . Facilitated diffusion or active transport Rate of drug entry into cells Passive diffusion 5/1/2017 Drug concentration 3. A specificity for a certain molecular structure may promote competition in the presence of a similarity structured compound. Examples of substances that are active transported include amino acids, methyldopa, 5-FU, penicillamine and levodopa. 5/1/2017 Example: Levodopa for dopamine HO CH2 HO CH2 HO NH2 Dopamine • Useful in treating Parkinson’s Disease • Too polar to cross cell membranes and BBB 5/1/2017 CH2 CO2H C HO H NH2 Levodopa • More polar but is an amino acid • Carried across cell membranes by carrier proteins for amino acids • Decarboxylated in cell to dopamine Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Carrier Protein Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Cell Membrane Membrane Cell 5/1/2017 RECEPTOR Cell Membrane Cell 5/1/2017 Cell Membrane Cell 5/1/2017 Cell Membrane Cell 5/1/2017 Cell Membrane Cell 5/1/2017 Blood supply H2N Brain cells H2N COOH COOH Enzyme L-Dopa H2N BLOOD BRAIN BARRIER 5/1/2017 Dopamine 4. Convective Absorption The absorption of small molecules, with molecular radii less than about 4Ǻ , through water filled pores of biological membrane. 5. Ion-Pair Absorption The absorption of a relatively large organic anion through its combination with a relatively large cation to form an ion pair which will cross a waterorganic solvent interface and transfer to an organic phase. 5/1/2017 6- Endocytosis/Exocytosis • For macromolecules or large complexes endocytosis exocytosis 5/1/2017 5/1/2017 The pH-Partition Hypothesis on Drug Absorption – This theory provides a basic framework for understanding of drug absorption from the GIT and drug transport across the biological membrane. The principle points of this theory are: 1. The GIT and other biological membranes act as lipid barriers. 2. The un-ionized form of the acidic or basic drug is preferentially absorbed. 3. Most drugs are absorbed by passive diffusion. 4. The rate of drug absorption and the amount of drug absorbed are related to its oil-water partition coefficient, the more lipophilic the drug, the faster is its absorption. 5. Weak acidic and neutral drugs may be absorbed 5/1/2017 from stomach but basic drugs are not. IONIZATION (pKa) Ionization and pH at Absorption site The fraction of the drug existing in its unionized form in a solution is a function of both the dissociation constant and the pH of the solution at the absorption site. 5/1/2017 IONIZATION of DRUGS Drug Absorption & Transport Depends on: Drug solubility Partition coefficient Ionization Drug Transport is a Compromise Between: Increased H2O solubility of ionized Superior passage of unionized (undissociated) 5/1/2017 IONIZATION of DRUGS IN GENERAL: drugs pass through membranes in undissociated form but act as ions, if possible pKa range of 6 – 8 seems most favorable (for passive transport) 5/1/2017 5/1/2017 CALCULATION OF IONIZATION Ionizable drugs (weak acids & bases) do so, depending upon: • Dissociation constant (pKa) • pH of the environment 5/1/2017 WEAKLY ACIDIC DRUGS Ka acid 1 5/1/2017 base 2 conjugate acid 2 conjugate base 1 Henderson-Hasselbalch WEAKLY ACIDIC DRUGS 5/1/2017 WEAKLY BASIC DRUGS Autoprotolysis Constant of Water (Kw) Kw 5/1/2017 use this equation to define the Kb term on next slide WEAKLY BASIC DRUGS Kb base 1 5/1/2017 acid 2 conjugate acid 1 conjugate base 2 WEAKLY ACIDIC DRUGS % ionized = 100 1 + 10 pKa pH (pKa - pH) % ionized 5.4 6.4 7.4 8.4 7.4 7.4 7.4 7.4 100/1+10-2 = 100/1.01 = 99.01% 100/1+10-1 = 100/1.1 = 90.91% 50% 100/1+101 = 100/11 = 9.09% 9.4 7.4 100/1+102 = 100/101 5/1/2017 = 0.99% WEAKLY BASIC DRUGS % ionized = 100 1 + 10 (pH - pKa) pKa pH 5.4 7.4 % ionized 100/1+102 = 100/101 = 0.99% 6.4 7.4 8.4 7.4 7.4 7.4 100/1+101 = 100/11 9.4 7.4 100/1+10-2 = 100/1.01= 99.01% 5/1/2017 = 9.09% 50% 100/1+10-1 = 100/1.1 = 90.91% IONIZATION SUMMARY Remember For an acid drug, the smaller the pKa, the stronger the acid For a basic drug, the larger the pKa (i.e. the smaller the pKb), the stronger the base 5/1/2017 IONIZATION SUMMARY A useful relationship Acid strength may be expressed as Ka or Kb of its conjugate base. Ka of an acid may be calculated if Kb is known. Stronger the acid, the weaker its conjugate base. 5/1/2017 knowing pKa and pH allows determination of % ionization 5/1/2017 Acidic groups 100% ionized when pH is 2 units above pKa Basic groups 100% ionized when pH is 2 units below pKa Acidic drugs that are highly ionized at pH 7.4 H S Drug H N N O O O OH HO O O NH O S O NH2 5/1/2017 Penicillin G 2.76 ASA 3.49 Sulfisoxazole 5.00 O O N pKa All > 99% ionized Basic drugs that are highly ionized at pH 7.4 N O O OH Drug pKa Atropine 9.65 Procaine 8.80 Chlorcyclizine 8.15 O N O NH2 N Cl 5/1/2017 N All > 85% ionized Groups on receptors may also be highly ionized at pH 7.4 O Acidic groups pKa aspartic acid 3.7 glutamic acid 4.30 phosphoryl 1.00 OH HO NH2 O NH2 HO OH O O O HO P• OH 5/1/2017 All > 99% ionized Groups on receptors may also be highly ionized at pH 7.4 Basic groups NH2 H N H2N NH H2N pKa OH arginine 12.5 O lysine 10.5 glutamine 9.10 O H2N OH NH2 H2N OH O O All > 98% ionized 5/1/2017 IONIZATION Examples What does this pKa refer to? propranolol i.e. is there an acidic functional group? pKa = 9.45 Is drug acidic, basic, amphoteric? Kb base 1 What is the pKb? 5/1/2017 conjugate acid 1 acid 2 4.55 conjugate base 2 IONIZATION Examples sulfasalazine What do the pKa’s refer to? i.e. are there acidic and/or basic functional groups? pKa = 2.4, 9.7, 11.8 Ka acid 1 5/1/2017 base 2 conjugate acid 2 conjugate base 1 IONIZATION of POLYPROTIC DRUGS Polyprotic acids donate >1 proton Each dissociation stage has an equilibrium expression and therefore pKa. pKa1 7.4 pKa2 ~ 12 - 13 phenobarbital 5/1/2017 It becomes progressively more difficult to donate protons 5/1/2017 5/1/2017 Methamphetamine, with a pKa dissolved in a solution at pH 7.87: 5/1/2017 of 9.87, is diethylbarbituric has an unionized H:B form, and an ionized B: form. It has a pKa of 8.0, and is dissolved in fluid with a pH of 7: 5/1/2017 Change of the ionization state will affect: i. Movement from aqueous phase to lipid upon crossing a membrane ii. Movement from aqueous phase to hydrophobic binding pocket iii. Movement from aqueous phase to location adjacent to a charged or polar residue in an active site – In order to elicit a pharmacological effect, drugs must be sufficiently soluble in water to be absorbed and distributed throughout the body. They must also have sufficient lipophilicity to be able to pass through biological membranes. 5/1/2017 Water Solubility and Hydrogen Bonding – A stronger and important form of chemical bonding is the dipole-dipole bond, specific example of which is the hydrogen bond. – A dipole results from the unequal sharing of a pair of electrons making up a covalent bond. This occurs when the two atoms making up the covalent bond differ significantly in electronegativity. N .............. H H H O O ............ H S R H Hydrogen Bond Hydrogen bonding of an amine to water and a thiol to water – Water has a dipole moment, due to the 104.5 degree bond angle, and the pull of electronegative oxygen on the attached hydrogens. This induced polarity gives water a higher boiling point and melting point than other hydrides (e.g. H-S-H, hydrogen sulfide, is a gas at room temperature). This dipole also allows water to hydrogen bond, and in pure water, it H-bonds to itself, forming a lattice. 5/1/2017 – Ionized molecules carry charge and favor interaction with water dipoles making these molecules water-soluble. Other molecules, e.g., glucose, are not charged, but, have an uneven electron density and are thus polar molecules that interact with water dipoles and are freely soluble in water. – This association with water molecules makes these watersoluble compounds less soluble in oils, fat, and lipid. These types of molecules are said to be hydrophilic (water-liking). – In contrast, nonpolar and noncharged molecules tend to be much more lipid-soluble or hydrophobic (water-hating) or lipophilic (lipid-liking). 5/1/2017 Partition Coefficient (Lipid/Water Partition Coefficient) It is a means of expressing a drug's solubility is lipid versus water. A drug is added to a two-phase solution of oil (or other organic solvent like 1-octanol) and water, mixed, and the concentration of drug in the organic and water phases determined. The ratio of the two phases reflects the relative lipid/water solubility. How does one determine a drug’s partition coefficient? 1. Add drug 2. Equilibrate 3. Determine [Drug]org and [Drug]aqu Organic phase 5/1/2017 Aqueous phase 4. Calculate Korg/aqu Mathematically, Korg/aqu = [Drug]org [Drug]aqu Lipid-Water Partition Coefficient – The ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (representing the membrane); and an aqueous buffer, pH 7.4 (representing the plasma) 5/1/2017 Lipid-Water Partition Coefficient • The higher the lipid/water p.c. the greater the rate of transfer across the membrane – polarity of a drug, by increasing ionization will the lipid/ water p.c. – polarity of a drug, suppression of ionization will the lipid/ water p.c. 5/1/2017 Lipid-Water Partition Coefficient • The higher the lipid/water p.c. the greater the rate of transfer across the membrane – polarity of a drug, by increasing ionization will the lipid/ water p.c. – polarity of a drug, suppression of ionization will the lipid/ water p.c. 5/1/2017 A drug’s partition coefficient, Korg/aqu is an index of the drug’s lipophilicity. Log P = 1 means 10:1 Organic:Aqueous Log P = 0 means 1:1 Organic:Aqueous Log P = -1 means 1:10 Organic:Aqueous In general, assuming passive absorption Optimum CNS penetration around Log P = 2 +/- 0.7 Optimum Oral absorption around Log P = 1.8 Optimum Intestinal absorption Log P =1.35 Optimum Colonic absorption Log P = 1.32 Optimum Sub lingual absorption Log P = 5.5 5/1/2017 Optimum Percutaneous Log P = 2.6 (& low mw) – The partition ratio of a given drug will determine its solubility in plasma, its ability to traverse cell membranes, and which tissues it will reach. – Drugs must have some aqueous solubility since this is essential for absorption through membranes, and for the production of an adequate concentration at the site-of-action. A balance between hydrophilicity and lipohilicity is necessary. This must be taken into account when chemically modifying a drug for optimal activity. 5/1/2017 The relationship between physicochemical properties and drug action “Theoretical representations” Overton-Meyer Hypothesis o The hypothesis states that, the higher the partition ratio P, the higher the pharmacological effect. The Ferguson Principle o The concentration of a drug in plasma is directly proportional to its activity. o Ferguson Constant is represented by 5/1/2017 where: X – High thermodynamic activity means that the activity of the drug is based on its physicochemical properties only, such as in a gaseous anesthetic. Such 5/1/2017 are known as non-specific agents. drugs – Low thermodynamic activity means that the activity of the drug is based on its structure rather than physicochemical properties. – Agents in this category are called specific agents, and their activity at low concentrations infers that they have a specific receptor. 5/1/2017 Electronic Effects Hammett Substituent Constant (s) • • The constant (s) a measure of the e-withdrawing or edonating influence of substituents It can be measured experimentally and tabulated (e.g. s for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X X CO2H X=H 5/1/2017 CO2 + K H = Dissociation constant= [PhCO2 ] [PhCO2H] H Hammett Substituent Constant (s) X= electron withdrawing group (e.g. NO2) X = electron withdrawing group X X CO2H CO2 + H Charge is stabilized by X Equilibrium shifts to right KX > K H s X = log KX = logKX - logKH KH Positive value 5/1/2017 Hammett Substituent Constant (s) X= electron donating group (e.g. CH3) X =donating electron X = electron withdrawing group group X X CO2H CO2 + H Charge destabilized Equilibrium shifts to left KX < K H s X = log KX = logKX - logKH KH Negative value 5/1/2017 Hammett Substituent Coefficient 5/1/2017 5/1/2017 s value depends on inductive and resonance effects s value depends on whether the substituent is meta or para ortho values are invalid due to steric factors 5/1/2017 Linear free energy relationship 5/1/2017 ρ the slope of the line, is a proportionality constant pertaining to a given equilibrium. σ is a descriptor of the substituents (Hammett constant ). – The magnitude of σ gives the relative strength of the electron-withdrawing or -donating properties of the substituents. • σ is positive if the substituent is electronwithdrawing and negative if it is electron-donating. 5/1/2017 Some illustrative values of ρ Some illustrative values of σ 5/1/2017 Applications of the Hammett Equation 1. Prediction of the pKa of ionization equilibria. For benzoic acid derivatives: 5/1/2017 Given σmeta = 0.71 for nitro groups and σpara = - 0.13 for methyl groups, the calculated pKa=2.91, which compares favorably with the experimental value of 2.97. 5/1/2017 2. Selection of the substituents for optimum biological activity. e.g. QSAR relating the inhibition of bacterial growth by a series of sulfonamides A QSAR was developed based on the σ values of the substituents where C is the minimum concentration of compound that inhibited growth of E. coli. It was found that electron-withdrawing substituents 5/1/2017 favor inhibition of growth. Hansch Constant (p) Hansch derived constants for the contributions of substituents to the partition coefficient. The lipophilicity constant, π, is defined as: π = log Px - log PH = log (Px/PH) where Px is partition constant for the compound with X as substituent and PH is the partition constant for the parent. Tables of values of π for other substituents are available. 5/1/2017 p values for various substituents on aromatic rings CH3 t-Bu OH CONH2 CF3 0.52 1.68 -0.67 -1.49 Cl F 1.16 0.71 0.86 0.14 Theoretical Log P for chlorobenzene = log P for benzene + p for Cl = 2.13 + 0.71 = 2.84 5/1/2017 Br p values for various substituents on aromatic rings CH3 t-Bu OH CONH2 CF3 Cl 0.52 1.68 -0.67 -1.49 Br 1.16 0.71 0.86 0.14 Theoretical Log P for meta-chlorobenzamide = log P for benzene + p for Cl + p for CONH2 = 2.13 + 0.71 - 1.49 = 1.35 5/1/2017 F The following are the p values for various substituents on an aromatic ring: -CF3 (1.07), -Br (0.94), -OCH3 (-0.02), -CH2OH (-1.03). Which functional group listed above will increase the water solubility of the following drug the most (ie. we replace the R- group with one of the substituents). A) -CF3 (1.07) B) -Br (0.94) C) -OCH3 (-0.02) D) -CH2OH (-1.03) E) They will all make the drug equally lipophilic 5/1/2017 Steric Effects The third major factor that often must be considered in QSAR involves steric effects. For studies involving reactivity of organic compounds, a steric parameter, Es, was defined by Taft as : where k is the rate constant for the acid hydrolysis of esters of the type 5/1/2017 – Assuming the electronic effects of substituent X can be ignored, the size of X will affect the transition state and hence the rate of reaction. – By definition Es = 0 for X=H. – Tables of values of Es for other substituents are available. 5/1/2017 Steric Effects much harder to quantitate Examples are: Taft’s steric factor (Es) (~1956), experimental value based on rate constants an Molar refractivity (MR)--measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction— Verloop steric parameter--computer program uses bond angles, van der Waals radii, bond lengths 5/1/2017 Hansch Approach A drug's activity was really a function of two processes: 1. its transportation from point of entry to receptor site(s) (pharmacokinetics). 2. its interaction with the receptor (pharmacodynamics). – Hansch proposed that the ability of a drug to get through a membrane might be modeled by its partition coefficient between a lipid-type solvent and water 5/1/2017 The suggested model for a drug traveling through the body to its receptor site might be: log 1/C = -k(log P)2 + k'(log P) + k" where potency is expressed as log (1/C) and C is the concentration of a drug that provides some standard biological effect. This equation has the format for a parabola The significance of this observation is that an optimum hydrophobicity may exist. 5/1/2017 Log (1/C) o Log P Log P Optimum value of log P for anaesthetic activity = log Po 5/1/2017 – Accordingly several membranes may have to be traversed for compounds to get to the target site, and compounds with the greatest hydrophobicity will become localized in the membranes they encounter initially, thereby slowing their transit to the target site. – Hansch proposed also that there should be a linear free energy relationship (like the Hammett equation) between lipophilicity and drug activity and that this might be indicated by the partition coefficient 5/1/2017 Hansch Linear Free Energy Model Hansch has derived a general equation based on linear free-energy considerations. In this equation is the ability to incorporate parameters which encompass the full range of known biological requirements for drug activity. Among theses terms for biological transport, drug/enzyme binding energies and substituent effects (both electronic and steric). The most general form of Hansch equation is: 5/1/2017 log 1/C = -aπ2 + bπ + ρσ + c Log 1/C = k1P - k2P2 + k3s + k4Es + k5 Where activity expressed as 1/C, C = concentration, π is the Hansch constant (measure of lipophilicty), ρ is constant related to the given molecule, σ is the Hammett substituent constant which is a measure of the electronic effect. Es Taft’s constant 5/1/2017 Hansch Analysis • Look at size and sign for each component of the equation. • Values of r <<0.9 indicate equation not reliable • Accuracy depends on using enough analogs, accuracy of data, & choice of parameters. 5/1/2017 Examples for Hansch equations log 1/C = 1.22 p – 1.59 s + 7.89 (n = 22; r = 0.918) log 1/C = 0.398 p + 1.089 s + 1.03 Es + 4.541 (n = 9; r = 0.955) 5/1/2017 Examples: Adrenergic blocking activity of b-halo-b-arylamines Y X CH CH2 1 Log C = NRR' 1.22 p - 1.59 s + 7.89 Conclusions: • Activity increases if p is + (i.e. hydrophobic substituents) • Activity increases if s is negative (i.e. e-donating substituents) 5/1/2017 For the antibacterial activity of substituted phenols OH X log 1/C = 0.684 log P – 0.921σ + 0.268 5/1/2017 For a series of phosphonate esters, cholinesterase inhibitors O O P OCH2CH3 R O2N log K = -0.152 π – 1.68 σ + 4.053 Es + 7.212 Where K is the inhibition constant, σ is the Hammett substituent constant for aliphatic systems Es is the Taft steric constant. In this example steric effect of the substituents plays an important role. The bulkier groups cause a decrease in 5/1/2017 cholinesterase inhibition. 一For the antibacterial effects on gram-negative bacteria of a series of diguanidines: NH (CH2)n (NH-C-NH2)2 log 1/C = -0.081 π2 + 1.483 π – 1.578 5/1/2017 Example: Antimalarial activity of phenanthrene aminocarbinols CH2NHR'R" (HO)HC X Y 1 Log C = -0.015 (logP)2 + 0.14 logP + 0.27 SpX + 0.40 SpY + 0.65 SsX + 0.88 SsY + 2.34 Conclusions: • Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) • Parabolic equation implies an optimum log Po value for activity • Activity increases for hydrophobic substituents (esp. ring Y) • Activity increases for e-withdrawing substituents (esp. ring Y) 5/1/2017 Electronic effect Lipophilicityt Steric effect 3-D space formed by lipophilic, electronic and steric coordinates 5/1/2017 Quantitative Structure-Activity Relationships (QSAR): QSARs are mathematical relationships linking chemical structure and pharmacological activity in a quantitative manner for a series of compounds. Methods which can be used in QSAR include various regression and pattern recognition techniques. 5/1/2017 Quantitative Structure-Activity Relationship (QSAR) Models Set of Compounds Activity Data (Y) Molecular Descriptors (Xi) QSAR Y = f(Xi) Prediction 5/1/2017 Interpretation Report On: Stereochemistry of Drug Receptor Interaction • Drugs • Receptors • Drug receptors interactions • Effects of Stereochemistry of the drugs molecules on their action. ) درجات5( هـ6/6/1430 أخر موعد لتقديم البحث 5/1/2017 اإلختبارالفصلى سينعقد بحول هللا تعالى يوم األحد 7جمادى األخر1430هـ املوافق 31مارس 2009م الساعة السابعة صباحا بقاعة املطالعة 2 215أ 5/1/2017 Free-Wilson Analysis log (1/C) = S aixi + m xi: presence of group i (0 or 1) ai: activity group contribution of group i m: activity value of unsubstituted compound 5/1/2017 Free-Wilson Approach Advantages • No need for physicochemical constants or tables • Useful for structures with unusual substituents • Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method Disadvantages • A large number of analogues need to be synthesised to represent each different substituent and each different position of a substituent • It is difficult to rationalise why specific substituents are good or bad for activity • The effects of different substituents may not be additive (e.g. intramolecular interactions) 5/1/2017 Choosing suitable substituents Substituents must be chosen to satisfy the following criteria: • • • A range of values for each physicochemical property studied values must not be correlated for different properties (i.e. they must be orthogonal in value) at least 5 structures are required for each parameter studied Substituent H Me Et n-Pr p 0.00 0.56 1.02 1.50 MR 0.10 0.56 1.03 1.55 Substituent H Me OMe p 0.00 0.56 -0.02 MR 0.10 0.56 0.79 5/1/2017 n-Bu 2.13 1.96 Correlated values. Are any differences due to p or MR? NHCONH2 I CN -1.30 1.12 -0.57 1.37 1.39 0.63 No correlation in values Valid for analysing effects of p and MR. Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents Example: . . . . . .. . . . . . .. . . . . . . . . . + 1.0 +s -p CF3SO 2 .75 CN CH3SO2 SO 2NH2 NO2 .50 OCF3 .25 CO2H -2.0 -p -1.6 -1.2 -.8 -.4 F .4 I Br Cl .8 1.2 1.6 CH3CONH -.25 OH Me 2.0 +p Et t-Butyl OCH3 -.50 NMe 2 NH2 -.75 -s -p 5/1/2017 SF5 CF3 CH3CO CONH2 +s +p -1.0 - -s +p • Craig Plot • Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties • Choose a substituent from each quadrant to ensure orthogonality • Choose substituents with a range of values for each property 5/1/2017 • Topliss Scheme Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow) Example: Aromatic substituents H 4-Cl L 4-OMe L M E E 4-CH3 L M E M 3,4-Cl2 L E 4-But 3-Cl 3-Cl L E M 3-CF3-4-Cl 4-CF3 2,4-Cl2 3-NMe2 See Central Branch 2-Cl 4-NMe2 L E M 3-Me-4-NMe2 4-NH2 5/1/2017 3-CH3 4-NO2 4-F 3-CF3 4-NO2 3,5-Cl2 3-NO2 M 3-CF3-4-NO2 • Topliss Scheme Rationale Replace H with para-Cl (+p and +s) Act. +p and/or +s advantageous add second Cl to increase p and s further Little change favourable p unfavourable s replace with Me (+p and -s) Act. +p and/or +s disadvantageous replace with OMe (-p and -s) Further changes suggested based on arguments of p, s and steric strain 5/1/2017 • Topliss Scheme Aliphatic substituents CH3 L E H; CH2OCH3 ; CH2SO2CH3 i-Pr M Et L E L M Cyclopentyl E END CHCl2 ; CF3 ; CH2CF3 ; CH2SCH3 Ph ; CH2Ph 5/1/2017 M Cyclohexyl Cyclobutyl; cyclopropyl t-Bu CH2Ph CH2CH2Ph • Topliss Scheme Example Order of Synthesis SO2NH2 R 1 2 3 4 5 R H 4-Cl 3,4-Cl2 4-Br 4-NO2 Biological Activity High Potency M L E M M= More Activity L= Less Activity E = Equal Activity 5/1/2017 * • Topliss Scheme Example R N N N N Order of Synthesis CH2CH2CO2H 1 2 3 4 5 6 7 8 R H 4-Cl 4-MeO 3-Cl 3-CF 3 3-Br 3-I 3,5-Cl 2 Biological Activity High Potency L L M L M L M M= More Activity L= Less Activity E = Equal Activity 5/1/2017 * * * Drug targets Proteins Lipids Receptors Enzymes Carrier proteins Structural proteins (tubulin) Cell membrane lipids Nucleic acids DNA RNA Carbohydrates Cell surface carbohydrates Antigens and recognition molecules 5/1/2017 Drug targets • Drug targets are large molecules - macromolecules • Drugs are generally much smaller than their targets • Drugs interact with their targets by binding to binding sites • Binding sites are typically hydrophobic pockets on the surface of macromolecules • Binding bonds • Most drugs are in equilibrium between being bound and unbound to their target • Functional groups on the drug are involved in binding interactions and are called binding groups • Specific regions within the binding site that are involved in binding interactions are called binding 5/1/2017 regions interactions typically involve intermolecular Drug targets Binding regions Drug Binding groups Intermolecular bonds Binding site Binding site Drug Drug Macromolecular target Unbound drug 5/1/2017 Macromolecular target Bound drug Drug Receptor • A macromolecular component of a cell with which a drug interacts to produce a response (Usually a protein). • Globular proteins acting as a cell’s ‘letter boxes’ • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells • Transmit a message into the cell leading to a cellular effect • Different receptors messengers • specific for different chemical Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers 5/1/2017 Types of Protein Receptors 1. 2. 3. 4. Regulatory – change the activity of cellular enzymes Enzymes – may be inhibited or activated Transport – e.g. Na+ /K+ ATP’ase Structural – these form cell parts 5/1/2017 Structure and function of receptors Nerve Nerve Signal Messenger Receptor Response Nucleus 5/1/2017 Cell Cell Chemical Messengers Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body • Chemical messengers ‘switch undergoing a reaction 5/1/2017 on’ receptors without Structure and function of receptors Nerve 1 Blood supply Nerve 2 Hormone Neurotransmitters 5/1/2017 Mechanism Induced fit Messenger Messenger Messenger Cell Membrane Receptor Receptor Cell Cell Receptor Cell message Message 5/1/2017 Mechanism • Receptors contain a binding site (hollow or cleft in the receptor surface) that is recognised by the chemical messenger • Binding of the messenger involves intermolecular bonds • Binding results in an induced fit of the receptor protein • Change in receptor shape results in a ‘domino’ effect • Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell • Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound 5/1/2017 The binding site • A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzyme • Accepts and binds a chemical messenger • Contains amino acids which bind the messenger • No reaction or catalysis takes place Binding site Binding site ENZYME 5/1/2017 Messenger binding Messenger M Induced fit • Binding site is nearly the correct shape for the messenger • Binding alters the shape of the receptor (induced fit) • Altered receptor shape leads to further effects signal transduction 5/1/2017 Bonding Forces vdw interaction H-bond Binding site O Ser H ionic bond CO2 Asp Receptor 5/1/2017 Phe • Induced fit - Binding site alters shape to maximise intermolecular bonding Phe Phe O O H Ser CO2 Asp Intermolecular bonds not optimum length for maximum binding strength 5/1/2017 Induced Fit Ser H CO2 Asp Intermolecular bond lengths optimised Drug-Receptor Bonding Ionic : the strongest type of non-covalent bond. This results from the attraction of ions with opposite charges 5/1/2017 R1 H N R R2 O R3 5/1/2017 Ion-Dipole : results when there is an attraction between an ion and the partial charge of a dipole of the opposite polarity 5/1/2017 Dipole-Dipole : Here a partially positive atom in a dipole is attracted to a partially negative atom in another dipole. Hydrogen Bonding : A dipole-dipole interaction where on of the constituents is a hydrogen 5/1/2017 attached to a heteroatom. Hydrogen bonds – – – – – – Vary in strength Weaker than electrostatic interactions but stronger than van der Waals interactions A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O) The electron deficient hydrogen is usually attached to a heteroatom (O or N) The electron deficient hydrogen is called a hydrogen bond donor (HBD) The electron rich heteroatom is called a hydrogen bond acceptor (HBA) 5/1/2017 - + X H Drug Y Target HBD HBA Drug Y HBA + H X Target HBD Hydrogen bonds – The interaction involves orbitals and is directional – Optimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle between X, H and Y is 180o X Hybridised 1s orbital orbital HBD 5/1/2017 Y H Hybridised orbital HBA X H Y Hydrogen bonds • Examples of strong hydrogen bond acceptors - carboxylate ion, phosphate ion, tertiary amine • Examples of moderate hydrogen bond acceptors - carboxylic acid, amide oxygen, ketone, ester, ether, alcohol • Examples of poor hydrogen bond acceptors - sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine • Example of good hydrogen bond donors - Quaternary ammonium ion 5/1/2017 5/1/2017 Water can act as an H-bond Donor or Acceptor Donates H Accepts H Lone pair electrons 5/1/2017 Examples of H-bonding interactions 5/1/2017 5/1/2017 The Hydrophobic Effect : when two alkyl chains approach one another, water is extruded from the space in between them, resulting in an increase in entropy, and thus a decrease in energy. 5/1/2017 Charge-Transfer Complexes : a lone pair of electrons is "shared" with a neighboring group that has considerable π character. 5/1/2017 Van der Waals Forces : one carbon in a chain approaches another carbon on a neighboring chain, causing a perturbation known as an induced dipole. These opposite partial charges then attract one another. 5/1/2017 Drugs may also bind to receptors using covalent bonding. This may be a permanent bond, in which case the receptor or enzyme target is "killed", or it may be transient. 5/1/2017 Drug Interaction with Receptor Lock & Key Model – NT binds to receptor NT = key Receptor = lock NT Receptor A 5/1/2017 NT Receptor A 5/1/2017 NT Receptor A 5/1/2017 Receptor B NT Drug A Receptor A 5/1/2017 Drug B Receptor B HO HO Activates and b adrenoceptors ADRENALINE = CH CH2 N H CH3 OH PHENYLEPHRINE = HO * CH CH2 N H CH3 Activates adrenoceptors OH ISOPRENALINE = HO HO CH OH 5/1/2017 CH2 N H CH(CH3)2 * Activates b receptors -Adrenoceptor H-Bonding region H-Bonding region H-Bonding region 5/1/2017 Van der Waals bonding region Ionic bonding region -Adrenoceptor ADRENALINE 5/1/2017 b-Adrenoceptor ADRENALINE 5/1/2017 b-Adrenoceptor SALBUTAMOL 5/1/2017 -Adrenoceptor SALBUTAMOL 5/1/2017 -Adrenoceptor SALBUTAMOL 5/1/2017 Dose Response Relationships Dose = amount of drug administered to the patient Response = effect in the body produced by the drug Drug + Receptor Drug-Receptor Complex Response 5/1/2017 100 3 Response 50 0 4 2 1 ED50 Log Drug Concentration [Molar] KEY PARAMETERS 1. Dose required to produce any effect at all. 2. ED50 = effective dose to produce 50% response 3. Dose required to produce maximum effect 5/1/2017 4. Dose that produces a toxic response. Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy 5/1/2017 Potency vs Efficacy • Potency – how much drug is required to produce a certain effect. 100 Response 50 0 2 1 ED50 Log Drug Concentration [Molar] 5/1/2017 Relative Potency hydromorphone morphine codeine Analgesia aspirin 5/1/2017 Dose Potency vs Efficacy • Efficacy – how large an effect the drug produces. 100 Response 50 0 2 1 ED50 Log Drug Concentration [Molar] 5/1/2017 Agonists Drugs Drugs that interact with and activate receptors, they possess both affinity and efficacy. • • • • • Agonist binds reversibly to the binding site Similar intermolecular bonds formed as to natural messenger Induced fit alters the shape of the receptor in the same way as the normal messenger Receptor is activated Agonists are often similar in structure to the natural messenger Agonist Agonist Agonist Induced fit RE 5/1/2017 R RE Signal transduction 5/1/2017 Antagonists Drugs • Drugs that interact with receptors but do not change them. •They have affinity but no efficacy. • Two types: • Competitive (reversible) antagonists • Non competitive (irreversible) antagonists 5/1/2017 • Competitive (reversible) antagonists M An An RE • • • • • • • R Antagonist binds reversibly to the binding site Intermolecular bonds involved in binding Different induced fit means receptor is not activated No reaction takes place on antagonist Level of antagonism depends on strength of antagonist binding and concentration Messenger is blocked from the binding site Increasing the messenger concentration reverses antagonism 5/1/2017 5/1/2017 Non competitive (irreversible) antagonists X Covalent Bond X OH OH O Irreversible antagonism • • • • • Antagonist binds irreversibly to the binding site Different induced fit means that the receptor is not activated Covalent bond is formed between the drug and the receptor Messenger is blocked from the binding site Increasing messenger concentration does not reverse antagonism 5/1/2017 Non competitive (reversible) allosteric antagonists Binding site unrecognisable Binding site ACTIVE SITE (open) Receptor ENZYME Allosteric site Induced fit (open) Receptor ENZYME Antagonist • • • • • Antagonist binds reversibly to an allosteric site Intermolecular bonds formed between antagonist and binding site Induced fit alters the shape of the receptor Binding site is distorted and is not recognised by the messenger Increasing messenger concentration does not reverse 5/1/2017 antagonism Effectiveness, toxicity, lethality • ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves • TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect • LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects 5/1/2017 Quantification of drug safety Therapeutic Index = 5/1/2017 TD50 or LD50 ED50 Drug A 100 sleep death Percent 50 Responding 0 ED50 5/1/2017 LD50 dose Drug B 100 Percent Responding sleep death 50 0 ED50 5/1/2017 dose LD50 Stereochemical Aspects in Drug Receptor Interaction – Drug molecules must generally interact with biomolecules in a very specific way to elicit a pharmacological response. – Biomolecules are chiral, they often discriminate between isomers of a given drug molecule. – The stereochemistry of a drug can impact its ability to bind to its target. 5/1/2017 The reason for chiral recognition by drug receptors is a three-point interaction of the agonist or substrate with the receptor or enzyme active site, respectively. 5/1/2017 Examples: Only the (-) enantiomer of epinephrine has the OH group in the binding site, and therefore has a much more potent pressor activity. 5/1/2017 ▪ Enantiomers interact with living systems in very different ways and results for example in: − Different smell CH3 CH3 O O (S) (R) H2C H H CH3 CH2 H3C (R) Spearmint oil (S) caraway oil Mirror plane 5/1/2017 Olfactory sensors are chiral − Different taste Aspartame O O O H H O O N H3N O O CH3 H H H3N O H (R,R) 160 Times Sweeter than Sugar Bitter!! Taste buds are chiral 5/1/2017 O N O (S,S) H CH3 − Different drug effects • Biomolecules, thus, can discriminate between enantiomers (isomers) of a given drug molecule. • The net result is same or different pharmacologic/ pharmacokinetic/ toxicologic activities 5/1/2017 Biological Discrimination => 5/1/2017 THALIDOMIDE: DISASTROUS BIOLOGICAL ACTIVITY OF THE “WRONG” ENANTIOMER H H N N * H O (R)-isomer O O N O O N * O O H O (S)-isomer − In the 1960’s thalidomide was given as racemic mixture (RS) to pregnant women to reduce the effects of morning sickness. − This led to many disabilities in babies and early deaths in many cases. The photographs are both from ‘Molecule of the Month’ at Bristol University: 5/1/2017 http://www.chm.bris.ac.uk/motm/thalidomide/start.html − Later found that only the R-isomer can be used safely − In 1998 thalidomide has been approved by FDA to reduce the immune system’s inflammatory response in a host of illnesses, including arthritis, lupus, cancer, leprosy, and AIDs. 5/1/2017 O NHCH3 CH3NH O H H CF3 CF3 (S)-Fluoxetine (R)-Fluoxetine − The pure S enantiomer prevents migraines. − A racemic mixture of fluoxetine (sold antidepressant Prozac) doesn’t prevent migraines. HOOC OH HO (S) (S) C H2N as the COOH C Copyright© 1999, Michael J. Wovkulich. All rights reserved. H H OH L-Dopa Anti-Parkinson’s 5/1/2017 disease drug NH2 HO D-Dopa Biologically inactive has serious side effects Likewise, cis/trans isomers of cyclic compounds, or Z/E isomers of alkenes are also expected to have different binding potency and therefore also different biological activity. 5/1/2017 5/1/2017 OH OH HO HO HO E-DES (Active) Estradiol Z-DES (Inactive) OH OH OH HO Estradiol & E-DES overlay 5/1/2017 According to this theory, the "right" isomer is called the eutomer. The "wrong" isomer is called the distomer. The ratio of the activities of the eutomer and the distomer is called the eudismic ratio, and converting the equation to log form affords the eudismic index, EI. 5/1/2017 Acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with Acetylcholine esterases in the fully extended confirmation and in a different morefolded structure with the nicotinic receptors at ganglia and at neuromuscular junctions. – Gauche conformer = muscarinic – Anti conformer = nicotinic 5/1/2017 Conformation is a spatial arrangement of a molecule of a given constitution and configuration. 5/1/2017 Life is Chiral COOH COOH C R H NH2 C R H NH2 • Proteins are built from L-amino acids, which implies that enzymes - the catalysts of nature - are chiral • Consequently, most biomolecules are chiral (sugars, DNA, proteins, amino acids, steroids) • Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer • This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the 5/1/2017 body. Stereochemistry Ph Ph HC OH HC NHCH3 CH H C NH HO CH H3CHN CH CH3 CH3 CH3 Ephedrine Ph Ph HO HC CH HC H3CHN NHCH3 o (mp = 76 C, []D = -50 ) H2 C N+ H H C OH OH 5/1/2017 X Receptor -(-)-Epinephrine Ephedrine (more active) - more active Diastereoisomers: Optical isomers which are not mirror images – Racemates: Mixture of equal parts of enantiomers CH Pressor activities of ephedrines Isomer H OH Anionic site – OH L(+) Pseudoephedrine D(-) Pseudoephedrine H 3C isomers CH3 CH3 o Enantiomers: Optical which are mirror images L(+) Ephedrine D(-) Ephedrine (mp = 40oC, []D = -6o) OH CH3 – Flat Area D (-) Pseudoephedrine DL Pseudoephedrine L (+) Pseudoephedrine L (+) Ephedrine DL Ephedrine D (-) Ephedrine Relative Activity 1 4 7 11 26 36