User:Nuklear/Indatraline
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[edit] Drug Kinetics
(Eliot Gardner, et al. 2006)[1]
Research on indatraline has also been made possible by NIDA contributions to increase the arsenal of medicaments with potential utility in the treatment of cocaine addiction.
[edit] Duration of Action
The short half-life (and hence duration of action) of methylphenidate and meperidine can be accounted for on the basis of the methylester that both of these drugs contain, which is relatively easily hydrolyzed to inactive metabolites (ritalinic acid, and meperidinic acid, respectively).
In contrast to the aforementioned pair of compounds, the side-chain of indatraline is an unsubstituted phenyl group. Indatraline consequently has a relatively long duration of action based on the fact that it does not contain any weak-links that are suceptible to metabolic degradation in-vivo.
Likewise, amphetamine has a long duration of action but although it has pharmaceutical applications, it is judged to have an unacceptably high abuse propensity, especially for treating addicts. The reader is referred to any one of the recent papers by Rothman, et al. for alternative aryl-isopropylamine approaches to treating addiction. However, although compounds with a more balanced 5-HT/catecholamine releasing portfolio (e.g. β-naphthyl-isopropylamine) had a lessened risk for self-administration, the 5-HT2C agonist actions precludes their application since these compounds are anorexic and stimulant addicts may already have eating disorders.
MDMA and p-thiomethyl-amphetamine also possess this balanced 5-HT/catecholamine releasing portfolio of activity, as well as various of the halogenated amphetamine derivatives. The reasons why these are ineffective treatment options are many and varied and lie outside the scope of the present syllabus. In passing however, it deserves mention that many diet pills are structurally related to amphetamine. For example, sibutramine, fenfluoramine, diethylpropion, phenmetrazine, phenylpropanolamine, phentermine, as well as ephedrine.
Due to the fact that methadone has demonstrated unequivocal efficacy in treating heroin addiction, it has been reasoned that a similar rationale can be applied for a triple reuptake inhibitor, of suitably long duration, in the treatment of cocaine addiction. None of the phenyltropane and amphetamine derived approaches have so far provided us with compounds that are of utility for rehabilitating stimulant abusers from their chaotic life styles. Any aroectic stimulant that functions as a robust reinforcer, serving to elevate blood pressure and that causes insomnia is likely to be judged as having an appropriate behavioral profile for the treatment of addicts. It is somewhat discouraging that indatraline also appears to share many of these liabilities.
Also, see the compound from which sertraline was derived, tametraline, which does not have any chlorine atoms. Tametraline is a reasonably active NARI. Likewise, it is suggested that the dechlorinated analog of indatraline is also conceived.
[edit] Effect of N-Dealkylation
It can be seen that the alkaloid nitrogen of indatraline is a secondary amine. This is important due to the fact that the dimethylamine prodrug must first be demethylated in vivo before the compound becomes active at monoamine transporters. In this respect, various Me-N-alkyl groups were prepared; as predicted, these novel analogs were retarded in their onset.
The rationale for doing this is based on the fact that a rapid onset of action underlies an increased abuse potential. This helps account for the reasons why intravenous, smoked, and snorted methods of administration are far more addictive that the same substances taken orally or transdermally (e.g. nicotine).
However, the tertiary amine prodrugs of indatraline might be viewed as an excessive counter-measure. Nevertheless, it was still researched as a potential treatment strategy.
[edit] XR Drugs
Extended release (XR) preparations of various medications provides a good illustration of altered kinetics. XR medicines have a retarded initial onset of action although they only have to be administered once or twice daily instead of every four hours. This has been effective for underlining the short-comings of drugs with a relatively short duration of action. However, a preferable attainment of this longer duration of action that is sought should be provided by the switch to drugs with a built in resistance to metabolic deactivation. Thereto the XR 'band-aid' solution can then be dispensed with.
Also, bear in mind that transdermal patches are similar in principle to XR formulations. Here though the drug is absorbed through the skin which helps bypass "first-pass metabolism" which is particularly helpful. As a result of this, the once absorbed into the bloodstream the drugs do not come into contact with stomach acids and are less likely to be metabolized by the liver to the same extent as when taken orally. For this reason, the dosage that must be administered within a given time-frame is correspondingly less.
Phamaceutical preparations of XR formulations exist for, e.g. venlafaxine, methylphenidate, tramadol and various opiates. Users generally prefer the standardized "immediate release" format given the choice. However, where the XR formulation is an option, physicians tend to favor these. These is because XR formulations have a lower predisposition towards misuse, and may be chosen even in cases where the patient does not have a history of drug abuse.
Persons with a known history of drug abuse will be at a heightened risk of consuming the said substances for non-medicinal applications such as for the inducion of a euphoric state of conciousness. This in and of itself may not be sufficient grounds to justify the preparation of XR formulations of the active ingredients. More explicitly, users of drugs such as methylphenidate and oxycodone have been known to crush and "snort" their pills, and in some cases even inject, to get high. This provides a more convincing rationale for the introduction of XR formulations. It might even be argued that the drug maker has both a legal and a moral obligation to provide preventative 'safe-guards' to reduce the likelyhood of this from occuring. In some cases, there may even be a legal penalty to pay if they fail to respond appropriately by taking adequate counter-measures.
Alternatively, drugs that sting the users nose if the user attempts to snort them, thereby serving as a deterrant to this method of administration. Use of various polymers/binders can also frustrate the ability of users to prepare injectable solutions.
However, the intentional molestation or tampering of pills/capsules raises important ethical disputes in the trade-off between hampering efforts to abuse a substance (and the corresponding increased harm reduction), versus denying people of their personal liberties (which is likewise damaging).
Examples of drugs with built in altered kinetics are the varying types of benzodiazepam based sedatives.
[edit] Tackling Drug Addiction
Although the rights of the drug user are frequently ignored or neglected, the suggestion of heroin clinics to reduce the crime needed to fund an addicts lifestyle choices mean that society may be starting to adopt a more liberal attitude towards tackling drug misuse. Drug use is also alot more common than is often given credit. Anybody who drinks alcohol, smokes tobacco, or consumes caffeinated beverages, are all participating in the taking of drugs. Alcohol is particularly obvious example of drug abuse since it is clearly psychoactive, and the social costs resulting from its abuse are well recognized and have already been studied extensively. The fact that alcohol consumption is so common suggests that the use of drugs may be inevitable. Moreover, the social costs may actually be higher if attempts are made to ban drug use altogether (i.e. criminalization) instead of employing a more diplomatic approach towards overcoming these problems.
[edit] Synthetic Methods
Importantly, the synthetic schemes to these compounds always comes into play when considering making them in the laboratory. Sertraline has a somewhat hard synthesis and involves making an acid chloride, which although common, is certainly not that attractive to do. There is more than one synthetic road to indatraline, although both methods have an intermediate where instead of the amine group there is a ketone. One would intuitively expect that the compound is made by reductive amination with methylamine – wrong! By doing this one gets cis diastereochemistry whereas the trans isomers are the ones that are needed. So, in order to get the trans diastereomers one has to add the amine in a 'round-about' fashion: First the keto is reduced (NaBH4), then the hydroxy is made into a better leaving group (e.g. tosyl chloride), before finally displacing with the amine giving "Walden" inversion of stereochemistry (SN2).
The above modification is somewhat annoying and probably helps account for indatraline not being more well-known. Nevertheless, it is not prohibitively difficult to do. Likewise, the interested scholar is referred to the synthesis of fencamfamine for another interesting stimulant compound.
[edit] Health & Safety
Indatraline is a stimulant compound and therefore the fact that it causes weight loss, ie it causes anorexia, is an important consideration that should not be overlooked. Because of its long half-life, like amphetamine, it may also cause insomnia which would lead to further disruption if used frequently. Similar to amphetamines, such compounds may have the propensity to induce hypertension and are therefore not suitable for subjects already possessing elevated blood pressure (BP) and should be monitored closely in persons with other medical diseases due to increased risk of complications.
Last but not least, these compounds could changes in haematology upon their repeated administration.
[edit] Common Literature
Froimowitz, et al. (2000),[2] Bogeso, et al. (1986).[3]
Interestingly sertraline has cis-diastereochemistry whereas Indatraline is trans.
[edit] References
- ^ [1]Eliot L. Gardner et al. (2006) A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: Effects in laboratory rat models relating to addiction. Neuropharmacology, Volume 51, Issue 5, Pages 993-1003.
- ^ [2]Mark Froimowitz, et al. (2000) Slow-Onset, Long-Duration 3-(3',4'-Dichlorophenyl)-1-indanamine Monoamine Reuptake Blockers as Potential Medications To Treat Cocaine Abuse. J. Med. Chem. 2000; 43(26); 4981-4992.
- ^ [3]Klaus Bogeso, et al. (1986) 3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake. J. Med. Chem. 28(12); 1817-1828.
