Receptor Pharmacology in 21st Century Therapeutics - Coursework Example

RECEPTOR PHARMACOLOGY IN 21ST CENTURY THERAPEUTICS due: Introduction From the beginning of the 20th century, there have been enormous leaps of development in the pharmaceutical industry and the science of pharmacology. Relentless research has led to the discovery of new synthetic drugs like barbiturates and syphilis curing arsenical compounds by scientists like Paul Ehrlich (Rang & Dale, 2012: 18). Further breakthroughs include the discovery of sulfonamides, which are the first antibacterial drugs and they were discovered by Gerhard Domagk, the development of penicillin by Florey and Chain based on Fleming’s work. Most of the hormones, inflammatory mediators and neurotransmitters known to man were discovered in the 20th and 21st centuries (Sneader, 2005: 388). Also, the realization that that chemical interaction plays an essential role in all the regulatory mechanisms of our bodies created an enormous area of common ground between pharmacology and physiology. The concept of receptors in pharmacology was also introduced in this era. A receptor, in pharmacology, is a cellular macromolecule that is concerned specifically and directly with chemical signaling within and between cells. Hormones, neurotransmitters and intracellular messengers cause a change in cellular activity to join receptors. The concept of receptors in pharmacology, together with its associated technologies, has boosted the field of therapeutics enormously due to the numerous occasions of drug discoveries (Kerkut & Gilbert, 1985: 384). History The discovery of the receptor concept has a long history. From long ago, man has always been intrigued by the ability of animals to differentiate between the smells and tastes of various substances (Gulini; et al 2000: 74). For example, in 50BC, Lucretius speculated that odours were conveyed by tiny particles, which had distinctive shapes in accordance to the substances they emanated from. Each type of particle would fit in specific spaces on the palate and the nostrils, thus receiving unique interpretation in the brain (Bailey, 1949, 45). The same theory of recognition sites complementing specific molecules is reiterated by John Locke in his work, Essay Concerning Human Understanding of 1690 (Mobilereference, 2008, 82). As prescient as they were, such theories could not be researched until the 19th century due to technological drawbacks. At this time, it becomes possible to disintegrate plant and animal materials while separating the individual components and purify them through fraction crystallization. This technology allowed scientists to obtain plant alkaloids like atropine, nicotine, strychnine, pilocarpine and morphine in a pure form. These and more substances proved to be invaluable resources in research on physiological function. For example, J.N. Langley used nicotine to activate then block the nerves that originate from the autonomic gangalia for the first time. His research allowed him to identify the divisions and distributions of the autonomic nervous system (Patil 2012: 281). Another scientist who was reaching similar conclusions at the time was Paul Ehrlich of Frankfurt. For the first time in history, he made a systematic research of the relationship between the biological actions of organic molecules and their chemical structures (Foye, Lemke, Williams 2013: 30). Together with organic chemist A. Bertheim, they organized and tested over 600 organo-metallic compounds that incorporated arsenic and mercury. Among the results of their research was the discovery of drugs such as salvarsan that destroyed pathogenic microorganisms responsible for diseases like syphilis. Paul Ehrlich also did some research on the selective staining of cells by dyes and the action of bacterial toxins. After all this research, he concluded that all biologically active molecules must bind to be effective. (Stephenson, 1956, 27). Due to their extensive and relentless research, Langley and Ehrlich are today recognized for their introduction of the receptor concept. Many other biochemists had also come to the conclusion that enzymes possess selective active sites among substrates and inhibitors. This shows that various numerous strands of evidence came to converge at a single conclusion. Major types of drug receptors 1. Trans-membrane ion channels The passage of hydrophilic molecules and ions across the plasma membrane is essential for all cellular functions. Specialized semi-permeable channels on the membranes regulate the passage of these substances. These ion channels have numerous roles including those in neurotransmission, muscle contraction, cardiac conduction and secretion (Golan & Tashjian 2012: 7). For this reason, drugs that act on ion channels can have some serious impacts on major body functioning. Three mechanisms are used to control the activity of the trans-membrane ion channel. One case is where the conductance is regulated by ligands binding to the channel (ligand-gated). The second case is where the conductance is controlled by changes in the voltage from the plasma membrane (voltage-gated). In the third case, the conductance is regulated by a ligand joined to the plasma membrane receptors linked to the channels (second messenger-regulated) (Nettles, et al, 2005, 63). Ion channels are highly selective of the ions they allow through. For example, the stimulation of the voltage gated channels permit the entry of Na+ ions into the cells. When the membrane charge to a neuron, it becomes positively charged to the sufficiency, the voltage gate channels for the Na+ ions open and allow an enormous influx of Na+ ions from without the cell to spill in, which depolarizes the cell further (Kenakin, 2007, 73). Many ion channels are similar in terms of structure in spite of their ion selectivity, magnitude of conductance, or mechanisms of activation and inactivation. The nicotine Ach receptor is perceived to assume only the states of being open and being closed, whereas other ion channels can assume other states on top of these two, like becoming refractory or inactivated. This state of inactivation lasts for a few milliseconds at which the channel cannot reactivate even when the potential resumes to a voltage that usually stimulates it in normal conditions. In this state, some drugs may bind with several other states of the same ion channel. This occurrence is called state-dependent-binding and is essential in the working of some drugs like antiarrhythmic drugs and anesthetics (Kew & Davies 2010: 254). Figure 1: four types of membrane associated drug targets 2. Trans-membrane G Protein-coupled Receptors These are the most common class of receptors in a human body. They are exposed at the surface on the exterior of the cell membrane. They traverse the cell membrane and possess intracellular areas that activate a class of signaling molecules referred to as G proteins. G protein coupled receptors possess seven trans-membrane areas in a single polypeptide chain (Iaizzo 2009: 192). Every transmembrane region has a single α helix and the helices are arranged in a motif that is similar in receptors of this type. The extracellular domain of these receptors mostly contains the ligand-binding area, though some G protein receptors link ligands in the receptor’s transmembrane domain. G proteins possess α and βγ subunits which are non-covalently bound in their resting state. The stimulation of a G protein receptor makes its cytoplasmic domain bind and activate a G protein while the α subunit exchanges GDP with GTP. The α-GTP subunit separate from the βγ subunit such that the α or the βγ subunits diffuses into the plasma membrane where they interact with various effectors including adenyl cyclase, some proteins and various ion channels. The signals produced by the G proteins are usually stopped by the conversion of GTP to GDP (Angers et al, 2002, 78). Figure 2: Receptor mediated activation of a G protein The activation of the second messengers is a major role of the G proteins. These proteins also activate the enzyme phospholipase C which is essential for controlling the concentration of intracellular calcium. Upon activation by the G protein, the enzyme cleaves the membrane PIP2 to the second messengers, DAG and IP3. IP 3 then triggers the expulsion of Ca2+ from the intracellular reserves thus increasing the cytosolic Ca (2+) concentration. DAG activates kinase C, which mediates other cellular activities including muscle contraction and ion transport. All these events are strategically regulated, such that the various steps in the pathways are activated and deactivated with characteristic kinetics. A lot of the Gα protein isoforms have been identified, each with its own unique effects on its targets. A few of such G proteins are G-stimulatory, G-inhibitory, Gq, Go, and G12. The variational functioning of these G proteins is likely to be essential for the selectivity of drugs in the future. The βγ subunits of G proteins also act as 2nd messenger molecules, even though their actions are not completely characterized in similar levels (Gether, 2000, 49). 3. Transmembrane Receptors with Enzymatic Cytosolic Domains The third major class of cellular drug targets entails the transmembrane receptors that bind a ligand from the outside of a cell with its interior, through the activation of a joined enzymatic domain. These receptors play roles in a wide array of physiologic workings, including growth, cell metabolism and differentiation. Receptors that possess an intracellular enzymatic domain are grouped into five major classes in accordance to their cytoplasmic mechanism of action. All these receptors are single membrane spanning proteins, unlike the seven membrane-spanning motif found in G protein receptors. Most receptors with enzymatic cytosolic domains structure into dimers or multi-subunit complexes. Most receptors with enzymatic cytosolic domains change proteins by adding or removing phosphate groups to or from selective amino acid residues. The negative charge of phosphate groups can change the three-dimensional form of a protein and thereby alter its activity. Furthermore, phosphorylation is reversible; thus it allows this signaling mechanism to take place specifically in time and space. Current therapeutic uses of receptors a). Research on epilepsy Research now shows that monogenically inherited epilepsy syndromes are involved in mutations that encode units of voltage gated and ligand gated ion channels. Idiopathic epilepsies are strongly linked to heritable mutations in GABA receptor subunits. G2 GABA receptor subunits mutations have been identified in two families having epilepsy syndromes (Blackburn 2010: 43, 44). A mutation associated with febrile seizures and regular epilepsy is in the loop connecting the TM2 on the exterior of the cells and TM3 domains. Research using recombinant receptors has showed that this mutant showed smaller GABA activated currents than did those receptors that lacked this mutation. The other mutation occurred in the rear section of the N terminus, which makes up part of the benzodiazepine-binding pocket and is associated with febrile seizures and childhood absence epilepsy. Research on frog oocytes showed that this mutation had reduced sensitivity to positive allosteric modulation. These findings were questioned frequently because of studies using a mammalian system of expression involving the HEK cells. They showed that the TM2-TM3 loop g2 GABA receptor mutation ended up in faster deactivation speeds while the N terminus mutant brought down the current amplitude without changing benzodiazepine sensitivity. Mutations within the cells of g2 GABA receptor subunits between TM1 and TM2 and between TM3 and TM4 have also been found to associate with epilepsy. Thus, all of the mutations in g2 GABAA receptor subunits may end up in reduced synaptic inhibition controlled by GABA receptors and epilepsy by various mechanisms. Even though heritable epilepsy represents only a small portion of epilepsies, the mutations associated with heritable epilepsy provide ideas as to possible predicaments with GABA receptors found in other epilepsies (Kenakin, 2002, 37). b). Research on sleep disorders GABA receptor systems are known to be very essential in sleep, and positive allosteric modulators of GABA receptors are highly used to find solutions for sleep disorders. Recent research indicates the importance of b3 GABA receptor subunits to sleep. An endogenous sleep promoting fatty acid called Oleamide is not active in b3 GABA receptor subunit knockout rats. A mutation in b3 GABA receptor subunits has been observed in a subject with chronic insomnia. A background check on this mutant showed a slower rate of desensitization than normal GABA receptors (Jenkinson, 2001, 37). Drugs that are used to treat insomnia include zolpidem, zaleplon and zopiclone. These drugs show some selectivity for a subunit that contains GABA receptors, acting as positive allosteric modulators. The structurally co-related indiplon, which is in phase III of clinical trials for the treatment of insomnia, works in a similarly selective mode. Gaboxadol, another drug in phase 3 of clinical trials, is a directly acting GABA receptor partial agonist, which interacts with a GABA receptor population that is not sensitive to zolpidem, benzodiazepines, zaleplon, indiplon and zolpidem. Many herbal prescriptions are obtained to promote sleep. For example, chamomile tea has flavonoid apigenin , which enhances the positive allosteric modulating actions of benzodiazepines on GABA receptors, while Valerian contains a variety of agents which act on GABA receptors (Clark, 2001, 56). Conclusion In the 20th and 21st century, the research on receptor function has made full use of the molecular biology revolution, and numerous discoveries are being made almost every day that challenge the seemingly simple discoveries made by pioneers such as Hill, Schild, Stephenson and other scientists. In the near future, the receptor concept will come to be recognized, not just as the big idea in pharmacology, but as one of the huge ideas in general biology. Living things are chemically driven, and work on chemical signaling both within and between cells, through the functioning of ligands and receptors. Making logic of the processes involved in these pathways is a crucial step to understanding biology. Pharmacologists can be proud of having started the ball rolling. Bibliography ANGERS, S., SALAHPOUR, A. & BOUVIER, M. (2002). Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu. Rev. Pharmacol. Toxicol., 42, 409–435. BLACK, J.W. & LEFF, P. 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