CHEMISTRY AND PHARMACOLOGY OF THE METHADOLS¹ AND ACETYLMETHADOLS²

Long-Term Pharmacotherapy for Opiate (Primarily Heroin) Addiction: Opioid Agonists

“…Chemistry, Pharmacokinetics, Pharmacodynamics, and Mechanisms of Action in Humans Acetylmethadol, as the racemic mixture, or as the opioid active or I and also nonopioid active d form, was synthesized and first studied for its possible analgesic actions and addiction liabilities in the late 1940s and early 1950s (BOCKMUHL and ERHART 1948;EDDY et al 1952;ISBELL 1951, 1952;KEATS and BEECHER 1952;SUNG and WAY 1954). l-a-acetylmethadol (LAAM) is a synthetic, acetylated, single enantiomeric congener of methadone which is even longer-acting in man (48h as contrasted to 24h), and like methadone, is orally effective, meeting the two major criteria for a pharmacotherapeutic agent for treatment of an addictive disease (KAlKa and INTURRISI 1973;KREEK 1973cKREEK , 1978aLEVINE et al 1973).…”

Heroin discriminative stimulus effects of methadone, LAAM and other isomers of acetylmethadol in rats

“…The other isomers of acetylmethadol tested, ad-acetylmethadol and b-d-acetylmethadol, were slightly more potent than LAAM at producing heroin's subjective effects and were previously reported to produce antinociception in mice (Eddy et al 1952). Conversely, b-lacetylmethadol, the isomer that failed to substitute completely for heroin's effects, has previously been reported to produce antinociception in mice.…”

“…Doses greater than 56 mg/kg b-l-methadol were not tested because of limitations in supply and it is possible that had higher doses been tested this drug would have demonstrated greater effects on response rate and in producing the heroin cue. Opiate-mediated antinociceptive effects of methadone are attributed to the l-methadone isomer (Eddy et al 1952), although some evidence suggests that d-methadone may produce antinociception via interaction with the NMDA receptor (Shimoyama et al 1997). d-Methadone is relatively behaviorally impotent, however; for instance, it fails to affect locomotor activity in mice at doses up to 50 mg/kg (Smits and Myers 1974).…”

“…Sodium propanol reduction of methadone's optical isomers gives rise to two methadols as described by Eddy and colleagues (Eddy et al 1952). Reduction of l-methadone yields two methadols, b-l-methadol and a-dmethadol.…”

Wagner Rearrangement of α-dl-6-Dimethylamino-4, 4-Diphenyl-3-Heptanol (α-dl-Methadol)

“…footnote 2) gives stilbenes of probably the trans configuration. 4 Compound IV was obtained (1) in the mild thionyl chloride treatment of I, while 111 was obtained by reaction of IV with phosphorus and hydriodic acid or by vigorous treatment of I with thionyl chloride, phosphorus pentachloride, phosphorus pentoxide, or phosphorus-hydriodic acid. 6 Melting points are corrected (Hershberg-type apparatus, total-immersion thermometers).…”