Acetylmethadols

When the ketone on carbon 5 of methadone is reduced to an alcohol, a second asymmetric carbon is developed (92). The four optically active isomers are known as (1) d-a-methadol, (2) d-/3-methadol, (3) Z-a-meth-adol, and (4) Z-(3-methadol. 

These compounds were recently developed (1952) and their pharmacology is incomplete. Reduction of d-methadone yields an a-methadol which is levorotatory. Acetyl-a-methadol is also levorotatory. Z-a-Meth-adol designates the levorotatory alcohol derived from d-methadone, and d-a-methadol the dextrorotatory alcohol derived from Z-methadone (92). Z-/3-Methadol designates the levorotatory alcohol from Z-methadone and d- -methadol the dextrorotatory alcohol from d-methadone. 

The a- and /3- racemic dZ-methadols are less effective than dZ-methadone the acetyl esters have toxicities similar to the parent compound, but produce more pronounced analgesia than does dZ-methadone (7). d-a-Afethadol and Z- -methadol were less effective than the parent compound Z-methadone. However, Z-a-methadol, Z-a-acetylmethadol, and d-/3 ac-etylmethadol exhibited analgesic activity when administered orally or subcutaneously these compounds are derived from d-methadone which has only slight analgesic activity (7). 

The racemic a-acetylmethadol (dZ-6-dimethylamino-4,4-diphenyl-3-acetyoxyheptane) has been studied clinically by David and Sender (93). When the racemic dZ-a-acetylmethadol was administered oraUy or subcutaneously to hospitalized patients, the average daily dose required to control pain adequately was 20-30 mg. given either in 5 mg. doses four or five times daily or 10 mg. two or three times daily. Some cumulative action 

Five to 20 mg. of d- -acetylmethadol subcutaneously led within 15 min. to effects which were subjectively pleasing to the patients. The effects had disappeared mthin 24 hr. Fifteen to 20 mg. of d-a-acetylmethadol orally yielded no evidence of morphine-like effects and no subjective reports of pleasurable sensations were obtained. 

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Acetophenazine 383 Acetyl methoxprazine 1, 131 Acetylmethadol 1, 81 Aclomethasone 3, 96 Actodigin 3, 97 Acyclovir 229... 

LAAM (L-a-acetylmethadol or levomethadyl acetate) is a full agonist at the i opioid receptor with pharmacologic properties similar to those of methadone. A number of studies have demonstrated that treatment with LAAM results in reduction of opioid use and beneficial effects comparable to those achieved with methadone (Ling et al. 1978 Tennant et al. 1986 Zangwell et al. 1986). However, retention rates are higher in patients who take methadone doses of 80—100 mg/day. 

Note. LAAM = L-a-acetylmethadol (no longer available in the United States). 

Kang J, Chen XL, Wang H, et al Interactions of the narcotic 1-alpha-acetylmethadol with human cardiac K+ channels. Eur J Pharmacol 458 25-29, 2003 Katchman AN, McGroary KA, Kilborn MJ, et al Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther 303 688-694, 2002... 

Tennant FS, Rawson RA, Pumphrey E, et al Clinical experiences with 959 opioid-dependent patients treated with levo-alpha-acetylmethadol (LAAM). J Suhst Abuse Treat 3 195-202, 1986... 

A somewhat related analgesic, noracymethadol (108), is an active metabolite of acetylmethadol. 

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

Acenocoumarole, 331 Acephylline, 425 Acetaminophen, 111 Acetanilide, 111 Acetazolamide, 249 Acetohexamide, 138 Acetophenazine, 383 Acetyl methoxyprazine, 131 Acetylcholine, as neurotransmitter, 62 Acetylmethadol, 81 Aches, minor, 85 Acylureas, as hypnotics, 95, 220, 245 Addiction... 

CYP, cytochrome P4SO LAAM, levo-alpha-acetylmethadol NSAID, non-steroidal anti-inflammatory drug PCP, phencyclidine. 

While there are extensive data on the use of methadone substitution therapy in adult opiate-dependent patients, there are only two published studies on opiate substitution therapy in adolescents and most of these subjects were 18 years of age or older (Hopfer et al., 2000). This lack of research is particularly concerning, given the recent increase in heroin use among adolescents (Hopfer et ah, 2000). Two newer substitution agents, L-oc acetylmethadol (LAAM) and buprenor-phine, offer alternatives to methadone, but remain untested in youth with SUD (Kranzler et al., 1999). 

Moreton, J. Edward, Timothy Roehrs, and Naim Khazan. 1976. "Drug Self-Administration and Sleep-Wake Activity in Rats Dependent on Morphine, Methadone, or L-Alpha-Acetylmethadol." Psychopharmacologia 47 237-41. 

Young, Gerald A., J. Edward Moreton, Leonard T. Meltzer, and Naim Khazan. 1977. "L-Alpha-Acetylmethadol (LAAM), Methadone, and Morphine Abstinence in Dependent Rats EEG and Behavioral Correlates." Drug and Alcohol Dependence2 141-48. 

Young, Gerald A., George F. Steinfels, and Naim Khazan. 1978. Transitional Patterns of Self-Administration Following Substitution of Methadone or L-Alpha-Acetylmethadol (LAAM) for Morphine in Dependent Rats." Drug and Alcohol Dependence 3 273-79. 

Rats Self-Ad ministering L-Alpha-Acetylmethadol (LAAM) or Morphine."... 

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)... 

Moody, D.E., Alburges, M.E., Parker, R.J., Collins, J.M., Strong, J.M. The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone, Drug Metab. Dispos. 1997, 25, 1347-1353. 

Walczak, S.A., Makman, M.H., Gardner, E.L. Acetylmethadol metabolites influence opiate receptors and adenylate cyclase in amygdala, Eur. J. Pharmacol. 1981, 72, 343-349. 

LAAM (LEVO-ALPHA-ACETYLMETHADOL) Like methadone, LAAM is a synthetic opiate used to treat heroin addiction, blunting withdrawal for up to 72 hours. 

Common Name Acemethadone Acetyldimepheptanol Acetylmethadol Amidolacetat Dimepheptanolacetat Methadyl acetate Race-Acetylmethadol... 

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