User:Nuklear

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Central nervous system (CNS) disorders account for some of the worlds best selling medications. Pain and depression constitute some of the most common visits to the doctor. Justifiably so then, non-addictive painkillers and improved antidepressants have a potentially huge market place. In contrast to temporal problems such as stomach upsets and the flu, pain and depression are often chronic affairs that will not necessarily resolve themselves if left untreated. Medications for these indications already exist, but their application is limited by drawbacks including risk of addiction, limited efficacy, and an unacceptable range of potentially serious side effects. Moreover, drug habituation may be the consequence of an addicts attempt to self-medicate, and is therefore intimately entwined with the pain and depression fields. Contrary to peripheral diseases, it is unlikely that regular exercize and a balanced diet can be considered effective strategies for the prevention and cure of CNS disorders. In light of this, the quest for new and improved chemicals to treat these indications, rightly remains a high priority.

Whereas in mainstream academia and major pharmaceutical companies, there is virtually unlimited access to the literature, articles can sometimes be difficult for private individuals and small companies to procure. Efforts have been made to keep the references within a manageable volume in accounting for this. Moreover, I want my work to have a more general appeal, and not only to be of interest to a narrow audience of readers. The documents are ordered in terms of their priority, although this obviously depends on an individuals specific interests. The documents also cannot be regarded as being completed, but they should nonetheless provide some interesting and hopefully novel insights, spurring on attempts for continued study and providing direction for future lines of enquiry. I am a medicinal chemist, nonetheless understanding of pharmacology and biological psychiatry also helps with the rationalization of drug discovery efforts.

SNDRI, Drug Combinations.

OMF, Phenyltropane, Nocaine.

Phenidate, Peridine, Indatraline.

1 Drug Discovery
2 External links
3 Recent Reviews
4 Scrapbook

[edit] Drug Discovery

When attempting to discover novel psychoactive drugs of medicinal utility, there are two roads that one may follow: (1) pharmacological information is gleaned from drugs that have demonstrated interesting and sometimes unexpected biological activity in behavioral tests, or (2) in a more deliberate fashion, known pharmacological information is applied with the express intent of designing more 'novel' drugs with pharmacological activities that are predetermined. As I will try to demonstrate by way of example, the two possibilities need not necessarily always be mutually exclusive, athough distinct parallels can be drawn between these two oppositional approaches.

The successful implementation of point (2) is dependent upon the availability, as well as the reliability and accuracy, of the QSAR information that is available in the literature at the time of attempting to make a 'discovery'.

Venlafaxine is an interesting case example of a surrendiptious drug discovery in that during its design it was initially tested as an opioid. Although tests for opioidergic bioactivity returned negative results, the authors were seemingly not deterred by this and continued studying its 'effects'. It eventually became apparent that the pharmacological mode of activity of venlafaxine is based on it inhibiting the reuptake of monoamines useful in the regulation of mood. Hence, venlafaxine turned-out to be an antidepressant and not the pain killer that it was originally envisaged to be (Yardley, et al. J Med Chem. 1990).

Several analogs of venlafaxine were prepared and different substitution patterns were found to differ in their affinity and selectivity ratios for the serotonin and noradrenaline transporters, respectively. This type of "library synthesis" is a common theme in drug discovery efforts, and provides valuable QSAR information. Ultimately though, a single molecule must be chosen out of a large number of possible candidates. The chosen molecule will then be subjected to lengthy and expensive clinical trials and more in-depth pharmacological studies will be undertaken until hopefully the novel drug will be licensed for a suitable indication and can then be officially prescribed to humans. It is not until this stage is reached that it is finally possible to make meaningful returns on the capital investment costs, which can total several hundred million $USD.

Based on the above considerations, it is crucially important that the appropriate selection choice was made initially. Even in cases where there are second thoughts, by that stage it may be too costly, both in terms of time and money, to turn back the clock and make a fresh start. For example, the p-bromo and m-chloro analogs of venlafaxine have a more balanced 5-HT/NA ratio, whereas venlafaxine (p-methoxy) is predominantly serotonergic. This may be an indication of the bias towards serotonergic theories of depression at the time; It is only more recently that the role of noradrenaline in treating the depressed syndrome has undergone a resurgence. Another recurrent observation is that the most potent drug in a particular drug class does not automatically qualify as being the one with the most acceptable therapeutic index. In this regard, the p,m-Cl₂ analog of venlafaxine was reported to be mutagenic in the paper quoted above.

Other examples of fortuitous drug discoveries include the AMPA potentiators (AMPAkines) and molecules such as modafinil dont easily fit into any of the existing drug classes. Point (1) constitutes the genuine inventions, whereas point (2) epitomizes "designer drug" molecules. A conflation of points (1) and (2) is where initial efforts attempt to secure known pharmacological properties at predetermined targets, although additional and unanticipated auxiliary activities are also discovered during follow-up investigations. The example already given for venlafaxine does not strictly satisfy this criteria in that for this to be correct it would have to function as an opioidergic SNRI (cf. tramadol). Therefore, although the discovery of venlafaxine satisfied point (1), point (2) was not met. Granted, venlafaxine does not obey the "morphine rule," several opioids discovered over the past few decades have been able to skirt this classic conjectural generalization.

Implementation of what will be referred to as the "hybridization principle" should lead to enhanced chances of securing a successful resolve versus an approach that has only satisfied either point (1) or point (2), but not both.

The fusion of more than one pharmacological activity into a single drug molecule is of great topical interest currently. The persual of highly selective agents is doubtless also important but for different reasons. The recent introduction of the opioidergic SNRI tapentadol is a high calibre example of point (2), which is structurally related to tramadol. [The interested reader can find out more about this via consultation of the relevant journal article/s.]

As already noted, in order to satisfy both point (1) and point (2) a hypothetical molecule with an anticipated mode of action must also confer fortuitous auxiliary activity on other pharmacological targets. This might thereby be thought to engender the molecule with unique pharmacological properties, and thus making it distinguishable from other molecules in its drug class.

In light of the discovery of tapentadol, other considerations need to be borne in mind when attempting to implement point (2) as opposed to 'stochastic' discoveries. This is becoming more the case than ever before, since due to information technology (IT) BOOM, there is much more theoretical planning than can be done beforehand than was the case during the 20th century. This is actually called the "in silica" phase of discovery, although it is a common misconception that this must involve expensive computer packages worth thousands of pounds. As was often the case with the earlier chess computers, a human brain is also able to calculate and make decisions. The difference is that chess is a relatively simple board game, whereas drug discovery, much like the human brain, is an 'organic' system, that is not easily solved with high-powered rigid calculations on supercomputers. Interestingly, there have been chemists (Newcastle) who have attempted to make molecules with silicon replacement of carbon in various designer organic drug molecules??

Tapentadol has a lessened risk of serotonin syndrome than tramadol because of its correspondingly weaker affinity for the SERT. In addition, tapentadol must not be first O-desmethylated in vivo, owing to the fact that this step has already been achieved chemically in vitro. This confers the resultant drug molecule with a more rapid and exact mechanism of action attending its administration. Furthermore, tapentadol is a single isomer whereas tramadol is a racemic pair of enantiomers. This significantly cuts the workload, due to the fact that in the research and development stages, each isomer must be treated as a separate drug. This is particularly true for tramadol, since each isomer is bioactive and it is not the case that one of the isomers is an simply inactive 'dummy'. Ofcourse, the O-methyl compound in the case of tapentadol can also be ignored, further adding to the simplicity and cost efficiency with which this designer drug molecule can be brought to market.

All of the above examples demonstrate a "designing out" of activity (SERT affinity, O-methyl group, and single isomer). This is incredible, since the SNDRI document deals almost exclusively with "add-on" strategies, and what we are witnessing here in the case of tapentadol is almost vice versa. Still, in good consonance, is the condensation of an opioidergic NARI profile into a single isomer, since in the case of tramadol, it was necessary to co-administer the racemic pair of enantiomers, in order to achieve this balanced portfolio of activity.

In addition to being an SSRI, escitalopram also has affinity for an allosteric binding site on the SERT, altering the conformation of the SERT active site in a manner that is complimentary to high affinity ligand docking/binding. This finding has been advertized in recent literature papers and used as a selling point by Lundbeck who hold patent rights for this compound. This example satisfies both points (1) and (2) although it is not especially interesting in that activity is still only confined to the SERT. As will be discussed further in the SNDRI document, the erosion of the SSRI market over recent years makes it unlikely that newer agents will be introduced to this drug class (Moltzen & Bang-Anderson, 2006).

Metabotropic receptors offer a rich and relatively untapped potential for drug discovery efforts. Inasmuch as these G-protein coupled receptors are still relatively under explored, QSAR information concerning these molecular targets is still in short-supply. There are 5 different subtypes of mGlu receptor and Eli Lilly have recently published work on their relevance to mood disorders, although they have utility in other CNS disorders such as pain (Witkin, et al. 2007).

Certain antidepressants such as bupropion possess affinity for various nicotinic receptor subtypes useful in improving cognition and likely also in reducing the sensitivity to painful stimuli. RTI-112 also has been shown to have nicotinic receptor subtype activity.

Thus in conclusion, 'novel' molecules with an anticipated (predetermined) mode of action (e.g. SNRI) may turn-out to have additional and unanticipated (fortuitous) pharmacological properties (e.g. AChR). Whether ir not this is does infact prove to be the case will only become manifest after more extensive pharmacological investigation, and thus should not be expected to become immediately apparent to the clan during the initial (preliminary) screenings.