Halogenation Of Amphetamine

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a1, most potent a1, most potent more lipophilic than theophylline and reputedly achieves higher brain concentrations. The half-life of caffeine is 5 to 8 hours, and that of theophylline, about 3.5 hours. About 1% of each compound is excreted unchanged. The compounds are metabolized in the liver. The major metabolite of caffeine is 1-methyluric acid, and that of theophylline, 1,3-di-methyluric acid.10 Neither compound is metabolized to uric acid, and they are not contraindicated in gout.


Sympathomimetic agents, whose effects are manifested mainly in the periphery, are discussed in Chapter 16. A few simple structural changes in these peripheral agents produce compounds that are more resistant to metabolism, more nonpolar, and better able to cross the blood-brain barrier. These effects increase the ratio of central to peripheral activity, and the agents are designated, somewhat arbitrarily, as central sympathomimetic agents.

In addition to CNS-stimulating effects, manifested as excitation and increased wakefulness, many central sympathomimetics exert an anorexiant effect. Central sympathomimetic (noradrenergic) action is often the basis for these effects. Other central effects, notably dopaminergic and serotoninergic effects, can be operative, however.11 In some agents, the ratio of excitation and increased wakefulness to anorexiant effects is decreased, and the agents are marketed as anorexiants. Representative structures of this group of compounds are given in Table 15.3. The structures of the anorexiants phendimetrazine and sibutramine and the alerting agents methylphenidate and pemoline, useful in attention-deficient disorders, are given in the text.

Structural features for many of the agents can be visualized easily by considering that within their structure, they contain a jS-phenethylamine moiety, and this grouping can give some selectivity for presynaptic or postsynaptic noradrenergic systems. jS-Phenethylamine, given peripherally, lacks central activity. Facile metabolic inactivation by monoamine oxidases (MAOs) is held responsible. Branching with lower alkyl groups on the carbon atom adjacent (a) to the amino nitrogen increases CNS rather than peripheral activity (e.g., amphetamine, presumably by retarding metabolism). The a branching generates a chiral center. The dextro(S)-isomer of amphetamine is up to 10 times as potent as the levo(R)-isomer for alerting activity and about twice as active as a psychotomimetic agent. Hydroxylation of the ring or hydroxylation on the jS-carbon (to the nitrogen) decreases activity, largely by decreasing the ability to cross the blood-brain barrier. For example, phenylpropanolamine, with a jS-hydroxyl (OH), has about 1/100th the ability to cross the blood-brain barrier of its deoxy congener, amphetamine.

Halogenation (F, Cl, Br) of the aromatic ring decreases sympathomimetic activity. Other activities may increase. p-Chloroamphetamine has strong central serotoninergic activity (and is a neurotoxin, destroying serotoninergic neurons in experimental animals).12,13

Methoxyl or methylenedioxy substitution on the ring tends to produce psychotomimetic agents, suggesting tro-pism for dopaminergic (D2) receptors.

N-methylation increases activity (e.g., compare metham-phetamine with dextroamphetamine). Di-N-methylation de

TABLE 15.3 Structures of Sympathomimetics with Significant Central Stimulant Activity

creases activity. Mono-N substituents larger than methyl decrease excitatory properties, but many compounds retain anorexiant properties. Consequently, some of these agents are used as anorexiants, reportedly with less abuse potential than amphetamine.

There can be some departure from the basic jS-phenethy-lamine structure when compounds act by indirect noradrenergic mechanisms. A jS-phenethylamine-like structure, however, can be visualized in such compounds.

The abuse potential of the more euphoriant and stimulatory of the amphetamines and amphetamine-like drugs is well documented. They produce an exceedingly destructive addiction. Apparently, both a euphoric "high" (possibly related to effects on hedonistic D2 receptors) and a post-euphoric depression (especially among amine-depleting drugs) contribute to compulsive use of these agents. Abuse of these drugs (especially methamphetamine) in recent years has reached disastrous proportions.

Recognized medical indications for dextroamphetamine and some very close congeners include narcolepsy, Parkinson disease, attention-deficient disorders, and, although not the preferred agents for obesity, appetite suppression. In some conditions, such as Parkinson disease, for which its main use is to decrease rigidity, the antidepressant effects of dextroamphetamine can be beneficial. It is also reportedly an effective antidepressant in terminal malignancies. In almost all cases of depression, and especially in major depressive disorders of the unipolar type, however, dextroamphetamine has long been superseded by other agents, notably the MAOIs and the monoamine reuptake-inhibiting antidepressants.

The compounds and their metabolites can have complex, multiple actions. In a fundamental sense, the structural basis for action is quite simple. The compounds and their metabolites resemble NE and can participate in the various neuronal and postsynaptic processes involving NE, such as synthesis, release, reuptake, and presynaptic and postsynaptic receptor activation. Also, because dopamine (DA) and, to a lesser extent, serotonin (5-hydroxytryptamine [5-HT]) bear a structural resemblance to NE, processes in DA- and 5-HT-activated systems can be affected. To illustrate the potential complexity, the receptor activations that can be associated with just one parameter, reduction in food intake, reportedly are a1, j1, jS2, 5-HT1B, 5-HT2A, 5-HT2C, Di, and D2.

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