Methadol

Modification of the ketonic side chain is also consistent with retention of analgesic activity. Thus, reduction of methadone with lithium aluminum hydride affords the alcohol, 128 (apparently as a single diastereomer). Acetylation gives acetyl-methadol (129). ... 

Oda, Y., Kharasch, E. D., Metabolism of methadone and levo-a-acetyl-methadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4) potential contribution of intestinal metabolism to presystemic clearance and bioactivation, J. Pharmacol. Exp. Ther. 2001, 298, 1021-1032. 

Table 5.10. HOT-PLATE ACTIVITIES IN MICE OF SOME METHADOLS AND NOR-METHADOLS BY SUBCUTANEOUS ROUTE (261, 262]...

Precursor Form Configuration Methadols (R = H) Acetylmethadols (r = COCH3)... 

A derivative of methadone, L-a-acetyl-methadol (LAAM) has been approved for the treatment of opioid addiction. In some addicts whose degree of tolerance is not known, the patient is first given methadone to stabilize the withdrawal signs and is then switched to LAAM. LAAM has an advantage over methadone in that it has a longer duration of action. Dosing is required only three times per week in most addicts to prevent withdrawal. 

There are not currently any medications that have been approved for treatment of MDMA addiction. In actuality, very few drugs of abuse have possible medical (pharmaceutical) treatments. Heroin addiction is one disease that is treatable by pharmaceutical means. Heroin addiction is often treated with methadone or levo-alpha-acetyl methadol (LAAM) administration. Similarly, alcohol addiction may be treated with pharmacological tools. However, most stimulants, such as cocaine, amphetamine, and MDMA, do not have medications available for treatment of addiction. 

Levo-alpha-acetyl methadol. A long-acting equivalent of methadone... 

Opioid receptor binding Levomethadyl acetate has a moderate affinity for opioid receptors with selectivity for the p-type. Higher binding affinity is induced by the active metabolites /-alpha-nor-acetylmethadol, nor-methadol and methadol (Walczak et al., 1981 Carroll, 1976). 

Pharmacokinetic properties Levomethadyl acetate is well absorbed from the intestinal tract and is extensively metabolized to various active metabolites, which contribute to the long duration of action. The metabolites nor-acytylmethadol, di-nor-acetylmethadol, nor-methadol, and methadol are formed by N-demethylation and hydrolytic cleavage of the ester bond (Moody et al., 1997)... 

Like methadone, LAAM (levo-alpha-acetyl-methadol) is a synthetic opiate used to treat heroin addiction. LAAM can block the effects of heroin for up to 72 hours. This makes outpatient treatment much more convenient, given that patients need to dose only two to three times a week. Naloxone and naltrexone are new medications that are also effective at blocking the pleasurable effects of heroin, helping motivated individuals to abstain. 

LAAM, the abbreviation of levo alpha acetyl methadol, is another opiate blocker that has been used to wean addicts. It persists up to 72 hours. 

These maintenance therapies supply regular doses of a drug that keeps the addict from experiencing withdrawal symptoms, drug cravings, or highs. Methadone and LAAM (levo-alpha-acetyl-methadol) are medications often used in these programs. 

Dimethylamino-4,4-diphenyl-3-heptanol (435.0 mg, 1.40 mmol) dissolved in ethyl acetate (10 ml) was treated with acetyl chloride (183.0 mg, 2.33 mmol). The mixture was refluxed for 2 h. After allowing the solution to cool to room temperature the solvent was removed under reduced pressure to leave a white foam, this crystallised from ethyl acetate to give 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane hydrochloride (levo-a-acetyl methadol hydrochloride) (420.0 mg, 79%). 

LAH reduces all three ketones and gives only one of the two possible diastereoisomeric alcohols designated the a-racemate in the cases of the branched chain ketones. The branched ketones give a//3 mixtures after treatment with sodium propanol from which the major (/3) isomer may be isolated. Similar results follow reduction of antipodal forms of methadone and isomethadone.(38) Both racemic methadols are inferior in potency to methadone (a, 0.08 yS, 0.2 methadone, 1) in the MHP test, but activity is more than restored on O-acetylation (a-acetate, 1.3 13-2). Racemic a-acety-... 

Table 9.5. Hot-plate Activities in Mice of Some Methadols and Normethadols (sc Route)...

Sullivan and others<17) found that a-(—)-N-desmethylmethadol and (—)-methadone were similarly potent as analgesics hence, the former represents an active metabolite of methadone (see p. 309). It is possible that the in vivo formation of the methadol (and the N-desmethyl analog) may account for the relatively better effectiveness of (+)-methadone as an analgesic when given orally rather than parenterally.<105)... 

High Pressure Liquid Chromatography. In plasma or urine levomethadyl acetate and metabolites, sensitivity 6 ng/ml for levomethadyl acetate, L-a-noracetylmethadol and methadol, 10 ng/ml for L-a-dinoracetylmethadol, normethadol, and dinor-methadol—C.- H. Kiang et al., J. Chromat., 1981, 222 Biomed. AppL, 11, 81-93. 

Disposition in the Body. Absorbed after oral administration. It is metabolised principally by A-demethylation to L-a-noracetylmethadol and L-a-dinoracetylmethadol which are active narcotics, and also by deacetylation to methadol which is also active further demethylation to normethadol and dinormethadol also occurs. L-a-Noracetylmethadol, L-a-dinoracetylmethadol and, in some subjects, unchanged drug accumulate during chronic oral administration, but there is considerable intersubject variation. About 20 to 25% of a dose is excreted in the urine as unchanged drug and demethylated metabolites, and about 2% as methadol and normethadol. 

---