Methadone analogs

The thiophene analog of methadone (253) and isomethadone have been prepared and shown to be active analgesies. Heterocyclic acetamides of the type (254) have been prepared for evaluation of their analgesic and antipyretic activity. - ... 

Replacement of the ketone by an amide leads to Increased potency. Hydrolysis of nitrile, 133 (obtained by alkylation of diphenylacetonitrile with the morpholine analog of the chloro-amine used in the original preparation of methadone), affords acid, 134. Conversion to the acid chloride followed by reaction with pyrrolidine affords racemoramide (135) Separation of the (+) isomer by optical resolution gives dextromoramide, an analgesic an order of magnitude more potent than methadone. 

Agonists include natural alkaloids of opium (morphine, codeine, and a large blend of natural alkaloids, pantopon, and omnopon), their analogs (hydrocodon and hydromor-phone, oxycodone, and oxymorphone), derivatives of morphinane (levorphanol), and a number of synthetic compounds derivatives of phenylpiperidine (meperidine, promedol), 4-anilidopiperidines (fentanyl, sufentanyl, alfentanil), and derivatives of diphenylheptane (methadone, propoxyphene). 

Slow-Onset, Long-Acting DA Substitution Strategy An Analogy to Methadone and LAAM for Opiate Substitution Therapy and to Slow-Onset Long-Acting Electrical Brain Stimulation Reward... 

Variants of the ethyl ketone function of methadone, an aspect already broached with mention of dextromoramide, include ester, sulphone, and secondary alcohol functions in addition to (-amides. The ethyl ester analog 14a obtained by treating the acid chloride derived from methadone cyanide with ethanol is markedly inferior in potency to methadone, while the sulfone 14b (obtained by aminoalkylation of benzhydryl ethyl sulfone) is equipotent... 

Little variation of the diphenylcarbon (—CPh2) unit of methadone has been reported. Removal of one phenyl abolishes activity 47 while its isosteric replacement by 2-thienyl gives a feebly active product/27 Strangely, some related 3-amino-l,l-di(2-thienyl)but-l-enes 16 (analogs of methadone with... 

Configurational data on diampromide and its relatives indicate, therefore, that the assumed analogy with the methadone class is not justified and that the two classes probably differ in their binding modes at the receptor.(91) Degrees of receptor stereoselectivity are generally less in the anilides (Table... 

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)... 

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