Chlorphentermin

The p-chloro analog of phentermine has much the same activity as the parent compound, with perhaps a somewhat decreased activity on the central nervous system. Alkylation of p-chloro-benzyl chloride with the carbanion obtained from treatment of 2-nitropropane with strong base affords the compound containing the required carbon skeleton (74). Catalytic reduction of the nitro group yields chlorphentermine (75). ... 

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

Figure 3 presents the mean levels of self-infusion for the 14 phenylethyl-amines shown in figure 1. Of all the drugs tested, injection rates were... 

In a summary of the human abuse literature on anorectic phenylethylamines, Griffiths et al. (1979) found there was a good correlation between the results of self-administration studies in animals and information about the subjective effects and abuse in man. Specifically, amphetamine, diethyl-propion, and phenmetrazine have been associated with numerous clinical case reports involving abuse, and these three compounds as well as benz-phetamine and /-ephedrine have shown similar subjective effects in drug abuser populations (Griffiths et al. 1979). In addition, fenfluramine was associated with low incidence of abuse in humans and did not maintain self-injection responding in animals. Chlorphentermine was similarly associated with low incidence of abuse in man, but did not maintain selfinjection uniformly in animals (Griffiths et al. 1979). 

Fig. 1.9 Structures of charge neutral (phosphatidylcholine) and acidic (phosphatidylserine) phospholipids together with the moderately lipophilic and basic drug chlorphentermine. The groupings R1 and R2 refer to the acyl chains of the lipid portions.

Table 1.1 shows the preferential binding of chlorphentermine to phosphatidylcholine-containing membranes, the phospholipid with overall acidic charge. These systems predict the actual affinity of the compound for the membrane, rather than its ability to cross the membrane. Membrane affinity, and hence tissue affinity, is particularly important in the persistence of drugs within the body, a topic which wiU be covered in Section 4.2. 

Tab. 1.1 Affinity ((t) and capacity (moles dmg/moles lipid) of chlorphentermine for liposomes prepared from phosphatidylcholine and phosphatidylserine.

Figure 3.19 Tissue distribution of chlorphentermine on chronic dosing. Source From Ref. 8.

The plasma level of a toxic compound is a particularly important parameter, as (i) it reflects and is affected by the absorption, distribution, metabolism, and excretion (ADME) of the compound (fi) it often reflects the concentration of compound at the target site more closely than the dose it should be noted that this may not always be the case such as when sequestration in a particular tissue occurs which may or may not be the target tissue, for example, chlorphentermine (see Fig. 3.19), lead and, polybrominated biphenyls (Fig. 3.20) ... 

The accumulation of fat is a common cellular response to toxic compounds, which is normally reversible. Usually triglycerides accumulate, although sometimes phospholipids accumulate, as occurs after exposure to the drug chlorphentermine (see chap. 2). Steatosis is particularly common in the liver as this organ has a major role in lipid metabolism (Fig. 6.15). The lipid may appear in the cell as many small droplets or as one large droplet. Interference with lipid metabolism can occur at several points ... 

It seems that for drugs to cause accumulation of phospholipids, the necessary physicochemical characteristic is the presence of both hydrophilic and lipophilic parts to the molecule, as exemplified by chlorphentermine (see chap. 3) (chap. 5, Fig. 1). They contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged (cationic) amine group. Such molecules are known as cationic amphipathic drugs or CADs. Other drugs, all in use, known to cause phospholipidosis are amiodarone, chloroquine (chap. 5, Fig. 1), tafenoquine, and gentamycin. 

In the case of chlorphentermine, it is believed to associate with the ionic portion of the phospholipids. Phospholipids are diglycerides with the remaining hydroxyl group of the glycerol esterified with a phosphate to which is attached a charged moiety such as choline. The long fatty acid chain is hydrophobic, the phosphate-choline is hydrophilic. They are particularly important constituents of membranes. 

Fig. 4.6 (A and B) Dependence of the drug-induced reduction of the transition temperature (A 7",) on the amount of chlorphentermine and clofibric acid added. The dissociation equilibrium of the drugs was shifted to the indicated forms by adjusting the pH of the liposome suspension to pH 6 and over pH 9 respectively (A). Dose-effect curves of the uncharged forms (pH 10 and pH 4.5, respectively. Dotted line indicates drug amounts at which morphologic alterations occurred in the liposome suspension (B). (Reprinted from Fig. 2 of ref. 96 with permission from Elsevier Science). (C) Liposomal binding of chlorphentermine and clofibric acid depending on the total amount of drug added to the liposome suspension (mean values of triplicate determinations). Maximum deviation from the mean was 10% of the mean. (Reprinted from Fig. 3 of ref. 96 with permission from Elsevier Science)...

Fig. 4.15 Accumulation of tritiated chlorphentermine and phentermine in the lungs of rats during chronic treatment with the indicated daily dosage. (Reprinted from Fig. 1 of ref. 133 with permission from Taylor Francis.)...

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