Phenethylamine Analogues Are Potentially Addictive

PhenethylamineAmphetamine was used to treat children with attention deficit disorder until its addictive potential was recognized. The fact that it could be abused led the physicians to do lots of research in order to come up with its substitute in medical field that did not have much adverse effects. However to the youths amphetamine has become a substance of abuse that many are familiar with. Here are details of the experiments, the substitutes or other the amphetamine analogues and how they work.

In an experiment Methylphenidate was found to inhibit competitively the striatal dopamine transporter (DAT) and bind at sites on the DAT in common with both cocaine (a non-substrate site ligand) and amphetamine (a substrate site ligand). Some methylphenidate analogues modified on the aromatic ring or at the nitrogen were tested to determine whether the profile of inhibition could be altered. None was found to stimulate the release of dopamine in the time frame of 60 seconds of the experiments conducted, and each of the analogues tested was found to noncompetitively inhibit the transport of dopamine. It was found that halogenating the aromatic ring with chlorine (threo-3, 4-dichloromethylphenidate hydrochloride; compound;

1) Increased the affinity of Methylphenidate to inhibit the transport of dopamine. A derivative of Methylphenidate with simultaneous, single methyl group substitutions on the phenyl ring and at the nitrogen (threo-N-methyl-4-methylphenidate hydrochloride; compound

2) Bound at a site in common with Methylphenidate. A benzyl group positioned at the nitrogen (three-N-benzylmethylphenidate hydrochloride; compound

3) Imparted properties to the inhibitor in which binding at substrate and non-substrate sites could be distinguished. This analogue bound at a mutually interacting site with that of methylphenidate and had a Kint value of 4.29 mM. Furthermore, the N-substituted analogues (compounds 2 and 3), although clearly inhibitors of dopamine transport, were found to attenuate dramatically the inhibition of dopamine transport by amphetamine, suggesting that the development of an antagonist for substrate analogue drugs of abuse may be possible.

PhenethylamineMethylphenidate is currently the most commonly prescribed drug to treat children with attention deficit disorder and is also used to treat narcolepsy. Originally, amphetamine was used to treat children with attention deficit disorder until its addictive potential was recognized. It was estimated in 1992 that 3% of school age children were being treated with Methylphenidate for some extended interval. These numbers have continued to increase. Methylphenidate is not thought to stimulate dopamine synthesis or induce release of dopamine from nerve terminals. The action of Methylphenidate is to block the inward transport of dopamine into the presynaptic terminal, resulting in a prolonged dopamine stimulus.

Although Methylphenidate, a psychomotor stimulant agent, has been shown to have abuse potential, it is still the drug of choice for the treatment of children with attention deficit disorder. Methylphenidate has been shown to bind at the dopamine transporter (DAT) and its binding is saturable and specific for the DAT but it is not clear where Methylphenidate binds on the transporter relative to dopamine and other inhibitors of transport.

Methylphenidate is thought to have behavioral, pharmacological, and binding properties similar to those of amphetamine. Therefore, Methylphenidate has been classified as a non-transported inhibitor of DAT as well as a substrate analogue for DAT when present at high concentrations these discrepancies have led to the current study, which focuses on comparing the inhibition properties and binding sites of Methylphenidate with those of some Methylphenidate structural analogues, amphetamine, and cocaine. The results of previous work by this laboratory in a kinetic model of the actively transporting DAT have shown that amphetamine and m-tyramine bind to the same site on the DAT and at a site competitive with dopamine .Thus, it was shown that amphetamine and m-tyramine are substrate analogues for the DAT. It was shown that amphetamine binds at a site that is separate but interacting with the inhibitory site of cocaine on the DAT.

Different Methylphenidate derivatives have been synthesized in an attempt to develop compounds that will block cocaine binding to the DAT but do not interfere with substrate binding or transport. The test used for their assessment has been to compare the IC50 for inhibition of the transport of dopamine with the IC50 of the test analogue for the displacement of [3H] WIN 35,428 binding.

In this current study, amphetamine, cocaine, and selected structural analogues of Methylphenidate were used to decipher whether Methylphenidate resembles amphetamine or cocaine in its effects on the function of DAT. The Methylphenidate derivatives studied in this work were chosen for their particular characteristics. Compound 1, a dichloro-substituted derivative, is one of the more potent Methylphenidate derivatives with respect to inhibition of [3H] WIN 35,428 binding. It differs from most other Methylphenidate derivatives that have been synthesized in that  it is equipotent as an inhibitor of [3H]WIN 35,428 binding and [3H]DA uptake and  it also has an equilibrium Hill coefficient (nH) determined against [3H]WIN 35,428 binding of dopamine. Most of the other Methylphenidate analogues are at least threefold less potent as inhibitors of [3H] DA uptake and have nH values of unity. Compounds 2 and 3 were included because they are some of the most effective analogues in discriminating between [3H] WIN 35,428 binding and [3H] DA uptake, with a five- to sevenfold separation in potency to inhibit binding versus transport.

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Phenethylamine Analogues Are Potentially Addictive