Section B- Drug targets Receptor types There are a large number of different receptors in the body that interact with and subtypes different chemical messengers. Three examples are receptors that are activated by acetylcholine(cholinergic receptors), receptors that are activated by epinephrine (adrenergic receptors), and those that are activated by dopamine(dopaminergic receptors). The various receptors show selectivity for one chemical messenger over another because they have binding sites of different shape, structure and amino acid composition. However, receptors that interact with one specific chem- ical messenger are not identical. For example, there are two types of adrenergic receptor-a-and B-adrenergic receptors. These receptors both bind epinephrine, but there are slight differences in their binding sites. This makes no difference as far as epinephrine is concerned, but it is very important when it comes to drug because it is possible esign aru adrenergic receptor than the other. Moreover, the different receptor types are not evenly distributed around the body. For example the heart has more p- than a adrenergic receptors. This means that drugs that are selective for B-adrenergic receptors will act on the heart rather than on tissues which are rich in a-adren- ergic receptors. Such selectivity is crucial in designing drugs with fewer side effects There are even subtle differences in the binding sites within a particular receptor type. For example, there are three subtypes of the B-adrenergic drugs with even greater selectivity. For example, lung tissue has a predono receptor(Br-, B2- and B3-subtypes). This provides the opportunity to desig nance of B2-adrenergic receptors, while heart tissue has a predo ominance drenergic receptors. Anti-asthmatic drugs that mimic epinephrine have been designed to interact with Bx-adrenergic receptors rather than pi-adrenergic receptors, so they interact with the adrenergic receptors in the lungs rather than those in the heart thus lowering cardiovascular side effects Agonists and Agonists are drugs that bind to the receptor binding site and mimic the natural antagonists messenger, by 'switching on the receptor. Binding produces the induced fit required to activate the receptor. Such drugs are useful if there is a lack of the natural chemical messenger. Antagonists are drugs that bind to the receptor binding site but do not activate the receptor, either because they fail to cause the required induced fit or because they distort the receptor in a different way. A bound antagonist prevents the natural messenger from binding, so the receptor can no longer receive messages. Antagonists are useful in blocking messages there is a surplus of the normal messenger lot all agonists and antagonists bind to a receptors binding site. Some antag- onists bind to a different region of the receptor and distort the protein such that the normal binding site is no longer recognized. This is equivalent to the allosteric inhibition of an enzyme. In some receptors, drugs can bind to an allosteric inding site and enhance the activity of the natural messenger. For example, the benzodiazepine tranquilizers act by potentiating the action of an inhibitory eurotransmitter called y-aminobutyric acid(GABA)at the GAba recept Side effects ide effects are usually caused when a drug binds to more than one type of receptor. Therefore, a major goal in drug design is to design drugs which will be as selective for one type(or subtype) of receptor as possible. For example, the serotonin receptor is the target for some antidepressant drugs. However, side effects can arise if these drugs interact with receptors for histamine or acetyl-
B2- Receptors All membrane bound receptors belong to one of the three follo bomne nd receptor ligand-gated ion channels G-protein-coupled receptors Kinase-linked recepto The mechanism by which a receptor conveys a signal to the cell depends on which family the receptor belongs to, and is called signal transduction LIgand-gated ion In this family of receptors, the receptor is an integral part of an ion channel (Fig channel 4). lon channels are protein complexes that traverse the cell membrane and form a tunnel through it. The function of an ion channel is to allow the flow of across the cell membrane and there are specific ion channels for sodium, potas sium, calcium and chloride ions. without ion tunnels ions could not cross the fatty cell membranes and this would have devastating effects on the chemistry of tration.However, the ion channels cannot be permanently open, since the uncon trolled flow of ions across the cell membrane would be as devastating as if they d not cross at all. Thus, ion channels are normally closed and are only opened when signaled to do so. This is where the receptor comes in, controlling whether the ion channel is open or closed binding site Y Induced fit and conformational membrane Fig 4. Ligand-gated ion channel receptors In the resting state, the ion channel is closed and the receptor's binding site is unoccupied. The signal to open the ion channel comes from the chemical messenger, which binds to the receptor and it to change shape as previ usly described. This change in shape is the start of a domino effect, which travels through the entire ion channel. The proteins making up the ion channel are normally positioned such that they seal the ion channel, but once the messenger receptor, the proteins alter their positions relative to each other, resulting in the channel opening up. lons can then flow through the channel. Once the chemical messenger leaves the receptor, the receptor and the ion channel reform their original shapes and block off the flow of ions. Such receptors are called ligand-gated ion channel receptors because the trigger for the process is a chemical messenger(the ligand), and the effect is to open up the 'gate sealing the ion channel. Since the receptor is an integral part of the ion channel, the effects of a receptor binding to its messenger are felt almost immediately by the cell as ions flow through the channel. Therefore, this mode of signal transmission is used when speedy communication is vital(e.g. when one nerve signals to another)
Section B- Drug targets G-protein-coupled The second family of receptors is the G-protein-coupled receptors(Fig. 5),so ceptor named because the receptor conveys a signal to the cell via a signaling protein alled a G protein. The G-protein-coupled receptor traverses the cell membrane with the binding site for the chemical messenger on the extracellular portion of e receptor. However, there is a second binding site on the intracellular portion of the receptor, which is specific for the G protein. This binding site is closed when the receptor is in the resting state Binding site Cell membrane Receptor G-protein Cell G-protein binding site tein- coupled receptors The G protein is made up of three subunits(a B, and y) and is free to move through the cell membrane. It also has a binding site which binds a nucleotide called guanosine diphosphate(GDP)(Fig. 6). In this state, the G protein is inert The method by which a receptor of this family conveys a message to the cell involves several stages (Fig. 7) 1.. A chemical messenger binds to the receptor and causes it to change shape This change in shape opens up the G-protein binding site. 2. The G protein binds to this binding site and the interaction between the ceptorand the g protein results in the g protein itself changing sha 3. The change of shape in the g protein alters the binding site for GDP such that it favors guanosine triphosphate(GTP)over GDP. As a result, GDP departs the G protein and gtp binds in its place 4. The binding interaction between the G Protein and GTP causes the protein to change shape yet again. This destabilizes the structure such that the a-subunit (along with GTP)splits off from the p-and Y-subunits. The subunit and the p, rdimer now leave the receptor. 。01o °。_B。B。B Guanosine dIphosphate(GDP) Fig. 6. GDP and GTP
B2-Receptors MEssenger CR GDP GTP 3 4。GTP 8. GTP Fg. 7. Activation of a G protein The receptor can now bind another G protein and so the process repeats itself for as long as the chemical messenger is bound to the receptor. This means that one chemical messenger can trigger the fragmentation of several G proteins. The a-subunit of the g protein now acts as a signaling unit. It floats through the membrane until it reaches a membrane-bound enzyme called adenylate cyclase (Fig 8). This enzyme has a binding site, which recognizes the a-subunit and binds it. The resulting induced fit causes the enzyme to change shape and its active site is opened. The reaction catalyzed by this enzyme is the conversion of adenosine triphosphate(ATP)to cyclic AMP (cyclic adenosine monophos- phate)(Fig 9). The reaction continues as long as the a-subunit is bound to the enzyme, which means that one a-subunit can lead to the synthesis of several clic AMP molecules-another amplification process. Cyclic AMP is produced in the cytoplasm of the cell and is an example of a secondary messenger. It triggers the start of a signaling cascade within the cell in which the signal is further amplified, leading to several different enzymes in the cell being acti vated or deactivated GTP Activ
Section B- Drug targets Adenylate cyclase ATP H Fig 9 Conversion of ATP to cyclic AMP The example given above shows the effect of a stimulatory G protein(Gs) where the a-subunit activates adenylate cyclase; but there ifferent G protein called a G; protein whose a-subunit inhibits adenylate cyclase. The Gs and G proteins are activated by different types of receptors, which are in turn activated by different chemical messengers. Thus, adenylate cyclase is under dual control. Whether the enzyme increases or decreases in activity will depen on whether the stimulatory or inhibitory G protein is in the ascendancy, which in turn depends on which kind of receptor is activated more strongly There is another type of G protein which works by activating a different embrane-bound enzyme called Phospholipase C(PLC). The catalyzed by this enzyme hydrolyses a component of the cell membrane itself, phosphatidylinositol diphosphate (PIPi), to generate two secondary messen- gers called inositol trisphosphate (])and diacylglycerol (DG)which proceed to initiate signaling cascades of their own (Fig. 10 Tyrosine kinase- Tyrosine kinase-linked receptors can be viewed as a receptor and enzym linked receptors into one receptor protein traverses the cell membrane and has an extracellular region and an intracellular region. The extracellular region acts as PLC HO⑥ PIP? 回-Po2 Fig. 10. Hydrolysis of phosphatidylinositol diphosphate