Drug Discovery and Development Essay Example

Drug Project


In the treatment of conditions such as depression, in some forms of personality disorder , and for the relief of anxiety, selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-specific reuptake inhibitors(SSRIS) and groups of compounds which are often prescribed. As described by Ferguson (2001) They act to relieve depression by raising the available amount outside cells of serotonin, a neurotransmitter . The reuptake of the available serotonin into the presynaptic cell is inhibited by the use of these drugs. This leaves more serotonin within the synaptic cleft and this is thereby free to be fixed to the postsynaptic receptor (Ferguson, 2001). Each of the available SSRIs, works in a slightly different way , and so their profiles as drugs also differ. This project will focus in particular on a candidate drug candidate which in the main is expedited using 5-hydroxytryptamine (HT) receptors (Catalyst.hcn.com.au.libraryproxy.griffith.edu.au, n.d., 2012).

Using the particular individual makeup of Escitalopram (Lexapro) as a foundation a candidate drug will be created .
Escitalopram is an active isomer of Citalopram and has been found to be more beneficial as a medication than other members of the SSRI group of drugs. (Catalyst.hcn.com.au.libraryproxy.griffith.edu.au, n.d., 2012). Escitalopram is taken each day and has a relatively short half-life, as compared with other anti-depressive drugs such as Prozac. This gives it the advantage in that it allows the changeover of drugs if needed much simpler. As compared with Lexapro any candidate drug would need to have less chance of side-effects, especially with regard to eliminating any possibility of lengthening of QT intervals. If these intervals are made longer as a result of medication then ventricular tachycardia may result. (Catalyst.hcn.com.au.libraryproxy.griffith.edu.au, n.d.2012). The most suitable method to choose was seen to be by taking a biological method in order to modify Lexapro, so that a drug could be produced with less tendency to create side effects.

In cases of depression the symptoms pathophysiology the person experiences would seem to indicate an imbalance in the neurotransmitters(MD, 2013). Symptoms described by people with depression include physical ones such as excessive tiredness, but these physical effects go together with negative mental ideas, feelings of worthlessness and guilt. The affected person has a complete change in attitude, and things they had previously enjoyed are no longer of any interest or pleasure. This negativeness is accompanied by sleep difficulties and also problems with concentration (MD, 2013). It can be seen therefore that depression affects a number of body systems in negative ways, causing changes in functions, and at the same time affecting mood and behaviour. Despite all these changes, which may at times be quite obvious, it can sometimes be hard to definitely diagnose someone as having depression (Pharmacologycorner.com, 2008).

Research has shown that the main factor which brings on depression is an upset in the action of CNS serotonin (5 HT) ( Ferguson, 2001). Although other neurotransmitters such as dopamine, glutamate and noradrenaline also play a part at times in depressive disorders and contribute to their severity (MD, 2013) it is the action of CNS 5-HT which plays the major part in more severe cases of depression. This can be demonstrated by the efficiency of the selective serotonin reuptake inhibitors (SSRI’s) (MD, 2013).

Seasonal affective disorder is a particular depressive disorder that comes into play when there are fewer daylight hours in autumn and throughout winter. Even without any medical help the condition will improve once the day lengthens in spring. (Emedicine.medscape.com, 2008). Studies seems to show that this form of depression is also influenced by alterations in CNS levels of 5-HT which are activated by changes in circadian rhythms, and the amount of available sunlight (MD, 2013).

The likelihood of depression increases as a person gets older, late –onset depression. This apparently occurs because the brain alters with age, and the person involved may also have acquired conditions such as cerebrovascular disease, and there may also be personal problems (MD, 2013). There may also be genetic components which increase the possibility of depression occurring. In the case of women who are menopausal, if they have already had a bout of depression, then their risk is higher. Despite this using hormone replacement therapy to increase levels of oestrogen gives no relief in this sort of depression. Amongst men, levels of testosterone decrease in later life, and this can be associated with episodes of depression (MD, 2013).

Over the years many attempts have been made to cure depression, using a variety of means. Electro convulsive therapy treated depression by acting directly at a neurobiological level, and was frequently used in the mid twentieth century (Watson and Goldman et al, 2007). Talking therapies such as psychotherapy and cognitive therapy were also used, but can be needed over extensive periods of time (MD, 2013). There are of course a number of anti-depressant medications including Citalopram , Fluoxetine, Escitalopram, and Paroxetine (Watson and Goldman et al, 2007). Other forms of anti-depressant medications include the TCA’s ( Tricyclic antidepressants) as well as SNRI’s (Serotonin and norepinephrine reuptake inhibitors). These can ease symptoms of irritability and low feelings of sadness. These drugs, although less effective than SSRI’s, work by inhibiting serotonin reuptake, but unfortunately can also result in the emergence of several serious side effects, and some of them are therefore classed as being ‘dangerous drugs’ (MD, 2013). Another group of medications, the MAO inhibitors( Monomine oxidase inhibitors) can also be used to relieve depressive symptoms. They are also degradation inhibitors, and were an earlier means of treatment for the depressive illnesses (Marshall, 2013).

The candidate drug is however considered to be capable of meeting previously unmet medical needs among depressive patients, including, but not necessarily being limited to, the lessening of the risk of negative side-effects which can be linked to the use of other anti-depressive medications used. The drug is only taken once daily and this increases compliance levels. The candidate drug, a reformulation of Escitalopram , must to be very effective . It will need to be capable of binding, as well as a high degree of lipophilicity. This would make it able to dissolve lipids with relative ease. This is needed if it is to easily travel across the blood brain divide (MD, 2013).

The research programme below is intended to find the best selective serotonin reuptake inhibitor which can be used in the treatment of depressive illnesses, acting by inhibiting the serotonergic synapse. This process will be explained in more detail in the various stages of the successful formulation of the new drug.


The serotonergic synapse is the primary target for all anti-depressant medications . This steering towards a particular aim has proved to be an effective was of causing inhibition in the re-uptake of serotonin by the pre-synaptic terminal. This then controls the level of serotonin within the brain, and this is then able to act to treat depressive symptoms (MD, 2013). The inhibitory drugs aim at the serotonergic synapse, but this is process can also be carried out also by both storage inhibitors and degradation inhibitors (Emedicine.medscape.com, 2008).

Diagram one (Ferguson, 2001)

Drug Discovery and Development

Serotonin 5-HT is the name given to set of receptors used in the diffusion of the serotonin neurotransmitters over the synaptic cleft (Ferguson, 2001). G-couple protein receptors are the members of 5-H group which most frequently used in the serotonergic synapse, and are pharmaceutically significant. As shown in diagram one, above, these presynaptic agents break down into three types of inhibitors, these being those which affect reuptake, storage and degradation.

The MAO inhibitor contained in degradation inhibitors , which acts as an enzyme for serotonin, noradrenaline, and dopamine (Skolnick, 2008). This includes medications such as phenelzine and tranylcypromine and. The enzyme inhibits the inactivation of the monoamines, and the result is that neurotransmitters are then able to cross over into the synaptic cleft (Skolnick, 2008). This method of treating depression was one of the earliest pharmaceutical methods to have been developed. It has the disadvantage of interacting negatively with certain foods. Its use therefore requires the patient to follow a restricted diet , and so is not widely used at the present time. Another negative aspect is that its use can result in hypertension (Skolnick, 2008).

The amphetamine group of medications, as well as methylphenidate and modafinil , inhibit storage by changing the storage capacity of monoamines in the synaptic vesicles The monoamines then replace serotonin within the terminals where they are stored. (Skolnick, 2008). They are used in mainly to treat those with sleep disorders and of those with ADHD and other behavioural disorders , but can have a positive effect upon depression (MJ, 2008).

In conclusion, the reuptake inhibitor is the commonest inhibitor in regular use is (MJ, 2008). It is used to prevent reuptake and results in there being higher concentrations of neurotransmitters within the synaptic cleft (Skolnick, 2008). In an attempt to treat depression three groups of drugs are used because of their effect upon this inhibitor. Most often SSRI’s are used, but SNRI’s and TCA’s are also utilised (MD, 2013). The SNRI (Effexor) works by blocking serotonin, as well as noradrenaline, from being re-taken up within the brain, and so can be effective in treating depression. SSRIs such as Prozac, Lexapro , and Zoloft work instead by blocking only serotonin reuptake (MD, 2013).
Among those studying this topic there is no definitive agreement as to whether it is SNRI’s or SSRI’s which are the more effective, and it seems possible that the degree of effectiveness depends upon individual circumstances (Watson and Goldman et al, 2007).

TCA’s (imipramine) can also be used in the treatment of depression. They work by blocking both noradrenaline and 5-HT, but it is SSRI’s which have more advantages when compared to TCA’s. They are better tolerated by patients, and, if an overdose does take place , the outcome will most often be more positive. In the most severe cases of depression SNRI’s and TCA’s are considered to more efficient, rather than using SSRI’s (Watson and Goldman et al, 2007).

The structure activity relationship (SAR) of serotonin receptors involves the use of benzene rings contained within each drug so that they are lipophilic, and , as a result, can cross the blood brain barrier (Nemeroff, 1988). If this lipophilicity was not present the drug could not bind itself to the 5-HT receptors and so reach the brain. At the present time Escitalopram has been found to have the highest ability to choose the binding site and is the most powerful, and therefore provides the greatest benefit among the available anti-depressants (Pharmacology Corner, 2008 ). The fluorine attached to the benzene ring, acts as a receptor with the serotonin receptor because of the ionic bonding which occurs (Catalyst.hcn.com.au.libraryproxy.griffith.edu.au, n.d.). Esitopro has a stable carbon-fluorine bod which delays both the metabolism and elimination of the drug, so it needs only to be taken once daily (Rxlist, 2013) Adding fluorine to the molecule increases. The degree of lipophilicity is altered because of the hydrophobic action of the carbon-fluorine bond (Pharmacology Corner, 2008 ). The amine group members also are hydrophobic in nature, and so have a place in improving the ability of the 5-HT receptors to bind in the same that fluorine does (Rxlist, 2013).

When comparisons of SSRI’s were carried out, so that a drug designed would be of the greatest benefit possible, four drugs were compared. These were citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil) and Escitalopram (Lexapro). All of these are successful medications when used to prevent , as well as treat both behavioural disorders and depression (Pharmacology Corner, 2008 ). After making comparisons of the various pharmacokinetic processes involved , as well considering any possible adverse effects and the dosages needed, it was concluded that Lexapro was the safest drug to use within the shortest time in order to reach a steady state. It has one of the lowest dosages of the group at 10-20mg/day. It is also the most selective of the medications considered, and has the lowest number of negative effects.

A common, and dangerous, side effect of taking anti-depressant medications is the possibility of lengthening the QT interval that is the time which taken from the beginning of the QRS complex to the end of the T wave, as can be seen when an electrocardiogram is carried out. (Mja.com.au, 2007). This represents the total duration of electrical activity within the ventricles (TheFreeDictionary.com, 2013).

The candidate drug should have target specificity. It also time needs to be highly efficient and to produce less side effects when compared to Lexapro (Mja.com.au, 2007). The drug produces less of a QT interval than is produced by Lexapro, and therefore minimising the risk of possibly fatal episode of torsades de pointes, more often known as ventricular tachycardia, (Pharmacologycorner.com, 2008). Lexapro is the favoured SSRI used by medical personnel at the present time. Lexapro will be reformulated to produce a candidate drug aimed at cutting side effects. If reformulated Lexapro will produce a better method of treating depression among the elderly, as higher dosages can safely be used. Testing and screening were carried out so as to find the most suitable potential candidate, capable of cutting down or eliminating the side effects produced by the SSRI’s in use at present. (Pharmacologycorner.com, 2008).

Concept Map

Drug Discovery and Development 1


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