Color Atlas of Pharmacology (Part 7): Drug-Receptor Interaction

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Color Atlas of Pharmacology (Part 7): Drug-Receptor Interaction

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Drug-Receptor Interaction partial charges. When a hydrogen atom bearing a partial positive charge bridges two atoms bearing a partial negative charge, a hydrogen bond is created. A van der Waals’ bond (B) is formed between apolar molecular groups that have come into close proximity. Spontaneous transient distortion of electron clouds (momentary faint dipole, !!) may induce an opposite dipole in the neighboring molecule. The van der Waals’ bond, therefore, is a form of electrostatic attraction, albeit of very low strength (inversely proportional to the seventh power of the distance). Hydrophobic interaction (C). The attraction between the dipoles of water is...

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  1. 58 Drug-Receptor Interaction Types of Binding Forces partial charges. When a hydrogen atom bearing a partial positive charge bridges Unless a drug comes into contact with two atoms bearing a partial negative intrinsic structures of the body, it can- charge, a hydrogen bond is created. not affect body function. A van der Waals’ bond (B) is Covalent bond. Two atoms enter a formed between apolar molecular covalent bond if each donates an elec- groups that have come into close prox- tron to a shared electron pair (cloud). imity. Spontaneous transient distortion This state is depicted in structural for- of electron clouds (momentary faint di- mulas by a dash. The covalent bond is pole, !!) may induce an opposite dipole “firm”, that is, not reversible or only in the neighboring molecule. The van poorly so. Few drugs are covalently der Waals’ bond, therefore, is a form of bound to biological structures. The electrostatic attraction, albeit of very bond, and possibly the effect, persist for low strength (inversely proportional to a long time after intake of a drug has the seventh power of the distance). been discontinued, making therapy dif- Hydrophobic interaction (C). The ficult to control. Examples include alky- attraction between the dipoles of water lating cytostatics (p. 298) or organo- is strong enough to hinder intercalation phosphates (p. 102). Conjugation reac- of any apolar (uncharged) molecules. By tions occurring in biotransformation al- tending towards each other, H2O mole- so represent a covalent linkage (e.g., to cules squeeze apolar particles from glucuronic acid, p. 38). their midst. Accordingly, in the organ- Noncovalent bond. There is no for- ism, apolar particles have an increased mation of a shared electron pair. The probability of staying in nonaqueous, bond is reversible and typical of most apolar surroundings, such as fatty acid drug-receptor interactions. Since a drug chains of cell membranes or apolar re- usually attaches to its site of action by gions of a receptor. multiple contacts, several of the types of bonds described below may participate. Electrostatic attraction (A). A pos- itive and negative charge attract each other. Ionic interaction: An ion is a particle charged either positively (cation) or negatively (anion), i.e., the atom lacks or has surplus electrons, respectively. At- traction between ions of opposite charge is inversely proportional to the square of the distance between them; it is the initial force drawing a charged drug to its binding site. Ionic bonds have a relatively high stability. Dipole-ion interaction: When bond electrons are asymmetrically distribut- ed over both atomic nuclei, one atom will bear a negative (!–), and its partner a positive (!+) partial charge. The mole- cule thus presents a positive and a nega- tive pole, i.e., has polarity or a dipole. A partial charge can interact electrostati- cally with an ion of opposite charge. Dipole-dipole interaction is the elec- trostatic attraction between opposite Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. Drug-Receptor Interaction 59 Drug + Binding site Complex + – + – D 50nm D Ion Ion Ionic bond !+ !– – !+ !– – D 1.5nm D Dipole (permanent) Ion !+ !– !– !+ !– !– D 0.5nm D !+ !+ D = Drug Dipole Dipole Hydrogen bond A. Electrostatic attraction !!+ !!– !!– !!+ D D !!– !!+ !!+ !!– Induced transient fluctuating dipoles B. van der Waals’ bond !+ "Repulsion" of apolar particle in polar solvent (H2O) !" apolar polar Phospholipid membrane Apolar acyl chain Insertion in apolar membrane interior Adsorption to apolar surface C. Hydrophobic interaction Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 60 Drug-Receptor Interaction Agonists – Antagonists tive receptor without causing a confor- mational change. An agonist has affinity (binding avidity) Agonist stabilizes spontaneously for its receptor and alters the receptor occurring active conformation. The protein in such a manner as to generate receptor can spontaneously “flip” into a stimulus that elicits a change in cell the active conformation. However, the function: “intrinsic activity“. The bio- statistical probability of this event is logical effect of the agonist, i.e., the usually so small that the cells do not re- change in cell function, depends on the veal signs of spontaneous receptor acti- efficiency of signal transduction steps vation. Selective binding of the agonist (p. 64, 66) initiated by the activated re- requires the receptor to be in the active ceptor. Some agonists attain a maximal conformation, thus promoting its exis- effect even when they occupy only a tence. The “antagonist” displays affinity small fraction of receptors (B, agonist only for the inactive state and stabilizes A). Other ligands (agonist B), possessing the latter. When the system shows min- equal affinity for the receptor but lower imal spontaneous activity, application activating capacity (lower intrinsic ac- of an antagonist will not produce a mea- tivity), are unable to produce a full max- surable effect. When the system has imal response even when all receptors high spontaneous activity, the antago- are occupied: lower efficacy. Ligand B is nist may cause an effect that is the op- a partial agonist. The potency of an ago- posite of that of the agonist: inverse ago- nist can be expressed in terms of the nist. concentration (EC50) at which the effect A “true” antagonist lacking intrinsic reaches one-half of its respective maxi- activity (“neutral antagonist”) displays mum. equal affinity for both the active and in- Antagonists (A) attenuate the ef- active states of the receptor and does fect of agonists, that is, their action is not alter basal activity of the cell. “anti-agonistic”. According to this model, a partial ago- Competitive antagonists possess nist shows lower selectivity for the ac- affinity for receptors, but binding to the tive state and, to some extent, also binds receptor does not lead to a change in to the receptor in its inactive state. cell function (zero intrinsic activity). When an agonist and a competitive Other Forms of Antagonism antagonist are present simultaneously, affinity and concentration of the two ri- Allosteric antagonism. The antagonist vals will determine the relative amount is bound outside the receptor agonist of each that is bound. Thus, although the binding site proper and induces a de- antagonist is present, increasing the crease in affinity of the agonist. It is also concentration of the agonist can restore possible that the allosteric deformation the full effect (C). However, in the pres- of the receptor increases affinity for an ence of the antagonist, the concentra- agonist, resulting in an allosteric syner- tion-response curve of the agonist is gism. shifted to higher concentrations (“right- Functional antagonism. Two ago- ward shift”). nists affect the same parameter (e.g., bronchial diameter) via different recep- Molecular Models of Agonist/Antagonist tors in the opposite direction (epineph- Action (A) rine dilation; histamine constric- tion). Agonist induces active conformation. The agonist binds to the inactive recep- tor and thereby causes a change from the resting conformation to the active state. The antagonist binds to the inac- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Drug-Receptor Interaction 61 Agonist Antagonist Antagonist Agonist Rare spontaneous transition Receptor inactive active Agonist Antagonist Antagonist Agonist induces active occupies receptor selects inactive selects active conformation of without con- receptor receptor receptor protein formational change conformation conformation A. Molecular mechanisms of drug-receptor interaction Receptors Increase in tension Agonist A Receptor occupation Efficacy EC50 EC50 Concentration (log) of agonist smooth muscle cell Agonist B Potency B. Potency and Efficacy of agonists Agonist effect 0 1 10 100 1000 10000 Concentration of antagonist Agonist concentration (log) C. Competitive antagonism Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 62 Drug-Receptor Interaction Enantioselectivity of Drug Action rinic ACh receptors almost 10000 times (p. 98) that of levetimide; and at !- Many drugs are racemates, including !- adrenoceptors, S(-)-propranolol has an blockers, nonsteroidal anti-inflammato- affinity 100 times that of the R(+)-form. ry agents, and anticholinergics (e.g., Enantioselectivity of intrinsic ac- benzetimide A). A racemate consists of tivity. The mode of attachment at the a molecule and its corresponding mirror receptor also determines whether an ef- image which, like the left and right fect is elicited and whether or not a sub- hand, cannot be superimposed. Such stance has intrinsic activity, i.e., acts as chiral (“handed”) pairs of molecules are an agonist or antagonist. For instance, referred to as enantiomers. Usually, (-) dobutamine is an agonist at "-adren- chirality is due to a carbon atom (C) oceptors whereas the (+)-enantiomer is linked to four different substituents an antagonist. (“asymmetric center”). Enantiomerism is Inverse enantioselectivity at an- a special case of stereoisomerism. Non- other receptor. An enantiomer may chiral stereoisomers are called diaster- possess an unfavorable configuration at eomers (e.g., quinidine/quinine). one receptor that may, however, be op- Bond lengths in enantiomers, but timal for interaction with another re- not in diastereomers, are the same. ceptor. In the case of dobutamine, the Therefore, enantiomers possess similar (+)-enantiomer has affinity at !-adreno- physicochemical properties (e.g., solu- ceptors 10 times higher than that of the bility, melting point) and both forms are (-)-enantiomer, both having agonist ac- usually obtained in equal amounts by tivity. However, the "-adrenoceptor chemical synthesis. As a result of enzy- stimulant action is due to the (-)-form matic activity, however, only one of the (see above). enantiomers is usually found in nature. As described for receptor interac- In solution, enantiomers rotate the tions, enantioselectivity may also be wave plane of linearly polarized light manifested in drug interactions with in opposite directions; hence they are enzymes and transport proteins. Enan- refered to as “dextro”- or “levo-rotatory”, tiomers may display different affinities designated by the prefixes d or (+) and l and reaction velocities. or (-), respectively. The direction of ro- Conclusion: The enantiomers of a tation gives no clue concerning the spa- racemate can differ sufficiently in their tial structure of enantiomers. The abso- pharmacodynamic and pharmacokinet- lute configuration, as determined by ic properties to constitute two distinct certain rules, is described by the prefix- drugs. es S and R. In some compounds, desig- nation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde. For drugs to exert biological ac- tions, contact with reaction partners in the body is required. When the reaction favors one of the enantiomers, enantio- selectivity is observed. Enantioselectivity of affinity. If a receptor has sites for three of the sub- stituents (symbolized in B by a cone, a sphere, and a cube) on the asymmetric carbon to attach to, only one of the enantiomers will have optimal fit. Its af- finity will then be higher. Thus, dexeti- mide displays an affinity at the musca- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Drug-Receptor Interaction 63 RACEMATE Benzetimide ENANTIOMER Ratio ENANTIOMER Dexetimide 1:1 Levetimide Physicochemical properties equal + 125° Deflection of polarized light - 125° (Dextrorotatory) ["] 20 D (Levorotatory S = sinister Absolute configuration R = rectus ca. 10 000 Potency 1 (rel. affinity at m-ACh-receptors A. Example of an enantiomeric pair with different affinity for A. a stereoselective receptor Transport protein C C A ff init y Transport protein Pharmacodynamic Intrinsic Turnover Pharmacokinetic properties activity rate properties B. Reasons for different pharmacological properties of enantiomers Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. 64 Drug-Receptor Interaction Receptor Types the GABAA subtype is linked to a chlo- ride channel (and also to a benzodiaze- Receptors are macromolecules that bind pine-binding site, see p. 227). Gluta- mediator substances and transduce this mate and glycine both act via ligand- binding into an effect, i.e., a change in gated ion channels. cell function. Receptors differ in terms The insulin receptor protein repre- of their structure and the manner in sents a ligand-operated enzyme (C), a which they translate occupancy by a li- catalytic receptor. When insulin binds gand into a cellular response (signal to the extracellular attachment site, a transduction). tyrosine kinase activity is “switched on” G-protein-coupled receptors (A) at the intracellular portion. Protein consist of an amino acid chain that phosphorylation leads to altered cell weaves in and out of the membrane in function via the assembly of other signal serpentine fashion. The extramembra- proteins. Receptors for growth hor- nal loop regions of the molecule may mones also belong to the catalytic re- possess sugar residues at different N- ceptor class. glycosylation sites. The seven !-helical Protein synthesis-regulating re- membrane-spanning domains probably ceptors (D) for steroids, thyroid hor- form a circle around a central pocket mone, and retinoic acid are found in the that carries the attachment sites for the cytosol and in the cell nucleus, respec- mediator substance. Binding of the me- tively. diator molecule or of a structurally re- Binding of hormone exposes a nor- lated agonist molecule induces a change mally hidden domain of the receptor in the conformation of the receptor pro- protein, thereby permitting the latter to tein, enabling the latter to interact with bind to a particular nucleotide sequence a G-protein (= guanyl nucleotide-bind- on a gene and to regulate its transcrip- ing protein). G-proteins lie at the inner tion. Transcription is usually initiated or leaf of the plasmalemma and consist of enhanced, rarely blocked. three subunits designated !, ", and #. There are various G-proteins that differ mainly with regard to their !-unit. As- sociation with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion chan- nel). A large number of mediator sub- stances act via G-protein-coupled re- ceptors (see p. 66 for more details). An example of a ligand-gated ion channel (B) is the nicotinic cholinocep- tor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two !-subunits results in opening of the ion channel, with entry of Na+ (and exit of some K+), membrane depolarization, and triggering of an action potential (p. 82). The ganglionic N-cholinoceptors apparently consist only of ! and " sub- units (!2"2). Some of the receptors for the transmitter #-aminobutyric acid (GABA) belong to this receptor family: Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. Drug-Receptor Interaction 65 Amino acids Agonist -NH2 H2N Effector protein 3 7 4 5 6 3 4 5 6 7 G- Protein COOH COOH !-Helices Transmembrane domains Effect A. G-Protein-coupled receptor Na+ K+ Insulin ACh ACh S S # $ ! ! S S S S " Nicotinic acetylcholine receptor Subunit Tyrosine kinase consisting of four trans- membrane Phosphorylation of Na+ K+ domains tyrosine-residues in proteins B. Ligand-gated ion channel C. Ligand-regulated enzyme Cytosol Nucleus Tran- scription Steroid Trans- Hormone lation Protein DNA mRNA Receptor D. Protein synthesis-regulating receptor Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. 66 Drug-Receptor Interaction Mode of Operation of G-Protein- 84). Phosphorylation of cardiac cal- Coupled Receptors cium-channel proteins increases the probability of channel opening during Signal transduction at G-protein-cou- membrane depolarization. It should be pled receptors uses essentially the same noted that cAMP is inactivated by phos- basic mechanisms (A). Agonist binding phodiesterase. Inhibitors of this enzyme to the receptor leads to a change in re- elevate intracellular cAMP concentra- ceptor protein conformation. This tion and elicit effects resembling those change propagates to the G-protein: the of epinephrine. !-subunit exchanges GDP for GTP, then The receptor protein itself may dissociates from the two other subunits, undergo phosphorylation, with a resul- associates with an effector protein, and tant loss of its ability to activate the as- alters its functional state. The !-subunit sociated G-protein. This is one of the slowly hydrolyzes bound GTP to GDP. mechanisms that contributes to a de- G!-GDP has no affinity for the effector crease in sensitivity of a cell during pro- protein and reassociates with the " and longed receptor stimulation by an ago- # subunits (A). G-proteins can undergo nist (desensitization). lateral diffusion in the membrane; they Activation of phospholipase C leads are not assigned to individual receptor to cleavage of the membrane phospho- proteins. However, a relation exists lipid phosphatidylinositol-4,5 bisphos- between receptor types and G-protein phate into inositol trisphosphate (IP3) types (B). Furthermore, the !-subunits and diacylglycerol (DAG). IP3 promotes of individual G-proteins are distinct in release of Ca2+ from storage organelles, terms of their affinity for different effec- whereby contraction of smooth muscle tor proteins, as well as the kind of influ- cells, breakdown of glycogen, or exocy- ence exerted on the effector protein. G!- tosis may be initiated. Diacylglycerol GTP of the GS-protein stimulates adeny- stimulates protein kinase C, which late cyclase, whereas G!-GTP of the Gi- phosphorylates certain serine- or threo- protein is inhibitory. The G-protein- nine-containing enzymes. coupled receptor family includes mus- The !-subunit of some G-proteins carinic cholinoceptors, adrenoceptors may induce opening of a channel pro- for norepinephrine and epinephrine, re- tein. In this manner, K+ channels can be ceptors for dopamine, histamine, serot- activated (e.g., ACh effect on sinus node, onin, glutamate, GABA, morphine, pros- p. 100; opioid action on neural impulse taglandins, leukotrienes, and many oth- transmission, p. 210). er mediators and hormones. Major effector proteins for G-pro- tein-coupled receptors include adeny- late cyclase (ATP intracellular mes- senger cAMP), phospholipase C (phos- phatidylinositol intracellular mes- sengers inositol trisphosphate and di- acylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentra- tion, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto func- tional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractil- ity of cardiac muscle, as well as in- creased glycogenolysis and lipolysis (p. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  10. Drug-Receptor Interaction 67 Receptor G-Protein Effector Agonist protein " " ! # ! # GDP GTP " " # ! # ! A. G-Protein-mediated effect of an agonist Adenylate cyclase DAG Phospholipase C Proteinkinase C Gs + - Gi Facilitation P of ion ATP P P channel cAMP opening IP3 Ca2+ Protein kinase A Transmembrane Activation ion movements Phosphorylation Phosphorylation of functional proteins of enzymes Effect on: e. g., Glycogenolysis e. g., Contraction e. g., Membrane lipolysis of smooth muscle, action potential, Ca-channel glandular homeostasis of activation secretion cellular ions B. G-Proteins, cellular messenger substances, and effects Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  11. 68 Drug-Receptor Interaction Time Course of Plasma Concentration The dose dependence of the time and Effect course of the drug effect is exploited when the duration of the effect is to be After the administration of a drug, its prolonged by administration of a dose concentration in plasma rises, reaches a in excess of that required for the effect. peak, and then declines gradually to the This is done in the case of penicillin G starting level, due to the processes of (p. 268), when a dosing interval of 8 h is distribution and elimination (p. 46). being recommended, although the drug Plasma concentration at a given point in is eliminated with a half-life of 30 min. time depends on the dose administered. This procedure is, of course, feasible on- Many drugs exhibit a linear relationship ly if supramaximal dosing is not asso- between plasma concentration and ciated with toxic effects. dose within the therapeutic range Futhermore it follows that a nearly (dose-linear kinetics; (A); note differ- constant effect can be achieved, al- ent scales on ordinate). However, the though the plasma level may fluctuate same does not apply to drugs whose greatly during the interval between elimination processes are already suffi- doses. ciently activated at therapeutic plasma The hyperbolic relationship be levels so as to preclude further propor- tween plasma concentration and effect tional increases in the rate of elimina- explains why the time course of the ef- tion when the concentration is in- fect, unlike that of the plasma concen- creased further. Under these conditions, tration, cannot be described in terms of a smaller proportion of the dose admin- a simple exponential function. A half- istered is eliminated per unit of time. life can be given for the processes of The time course of the effect and of drug absorption and elimination, hence the concentration in plasma are not for the change in plasma levels, but ge- identical, because the concentration- nerally not for the onset or decline of effect relationships obeys a hyperbolic the effect. function (B; cf. also p. 54). This means that the time course of the effect exhib- its dose dependence also in the pres- ence of dose-linear kinetics (C). In the lower dose range (example 1), the plasma level passes through a concentration range (0 0.9) in which the concentration effect relationship is quasi-linear. The respective time cours- es of plasma concentration and effect (A and C, left graphs) are very similar. However, if a high dose (100) is applied, there is an extended period of time dur- ing which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentra- tion does not cause a change in the size of the effect. Thus, at high doses (100), the time-effect curve exhibits a kind of plateau. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the in- tensity of the effect. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  12. Drug-Receptor Interaction 69 Concentration Concentration Concentration 1,0 10 100 0,5 5 50 t1 t1 t1 2 2 2 0,1 1 10 Time Time Time Dose = 1 Dose = 10 Dose = 100 A. Dose-linear kinetics 100 Effect 50 0 Concentration 1 10 20 30 40 50 60 70 80 90 100 B. Concentration-effect relationship Effect Effect Effect 100 100 100 50 50 50 10 10 10 Time Time Time Dose = 1 Dose = 10 Dose = 100 C. Dose dependence of the time course of effect Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
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