Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis.

The N-demethylation of LAAM, norLAAM, and methadone has been investigated in human liver microsomes and microsomes containing cDNA-expressed human P450s. Gas chromatography/mass spectrometry methods allowed detection of norLAAM and dinorLAAM formation from LAAM, dinorLAAM formation from norLAAM, and EDDP and EMDP formation from methadone. The rates of N-demethylation varied 4- to 7-fold in microsomes from four different donors with activities for LAAM and norLAAM consistently greater (5- to 14-fold) than for methadone. The N-demethylation of LAAM, norLAAM, and methadone were significantly inhibited by ketoconazole. IC50s could be determined for ketoconazole inhibition of LAAM and norLAAM N-demethylation of 1.6 and 1.1 microM, respectively. The ability of ketoconazole to reduce methadone N-demethylation below 40% varied in regard to liver donor. No other P450-selective inhibitors reduced the average activities more than 43%. cDNA-expressed P450 3A4 N-demethylated LAAM, norLAAM, and methadone at greater rates than the other cDNA-expressed P450s studied (1A2, 2C9, 2D6, or 2E1). P450 3A N-demethylation of LAAM, norLAAM, and methadone exceeded the next most active P450, respectively, by at least 2.5, 9.6, and 13.4 times when expressed per milligram protein and by 18.2, 6.0, and 6.1 times when expressed per nanomole P450. These results suggest that P450 3A4 is the primary site of N-demethylation of LAAM, norLAAM, and methadone in human liver. Although other enzymes may also be capable of N-demethylating these compounds, identification of specific enzymes, except P450 3A4, has yet to be established. Knowledge of these enzymatic pathways is essential for assessment of the impact of metabolic drug-drug interactions on therapeutic success and/or adverse events.

The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone.

History and current status of opioid maintenance treatments: blending conference session

Trees have made an enormous phytochemical contribution in anticancer drugs' development more than any other life form. The contributions include alkaloids that are biosynthesized in various ways and yield. Lead alkaloids isolated from the trees are taxol and camptothecins that currently have annual sales in billion dollars. Other important alkaloids isolated from these life forms include rohitukine, harringtonine, acronycine, thalicarpine, usambarensine, ellipticine, and matrines. Studies on their mechanism of action and target on the DNA and protein of cancerous cells aided the development of potent hemisynthesized congeners. The molecules and their congeners passed/are passing a long period of historical development before approved as antineoplastic drugs for cancer chemotherapy. Some of them did not find the application as anticancer drugs due to ineffectiveness in clinical trials; others are generating research interest in the antineoplastic activity at the present and have reached clinical trial stages. Potentials in antineoplastic molecules from trees are high and are hoped to be commensurate with cancer types afflicting human society in the future.

Anticancer Alkaloids from Trees: Development into Drugs

Methadone and levo -α-acetylmethadol (LAAM) are opioid agonists used for analgesia and preventing opiate withdrawal. Methadone is sequentially N -demethylated to the inactive metabolites 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP). LAAM is essentially a prodrug that undergoes bioactivation via sequential N -demethylation to levo -α-acetyl- N -normethadol (nor-LAAM) and levo -α-acetyl- N , N -dinormethadol (dinor-LAAM). Methadone and LAAM are metabolized by CYP3A4 in human liver. Since they are administered orally, and CYP3A4 is expressed in human intestine, we tested the hypotheses that human intestine can metabolize methadone and LAAM, and evaluated the participation of CYP3A4. Intestinal microsomal methadone N -demethylation exhibited hyperbolic noncooperative kinetics and biphasic Eadie-Hofstee plots. Using a dual-enzyme Michaelis-Menten model, K m values were 11 and 1200 μM for EDDP and 23 and 930 μM for EMDP formation, respectively. CYP3A4 inhibitors (troleandomycin and ketoconazole) inhibited EDDP and EMDP formation by >70%. Methadone N -demethylation by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; K m values were 10 and 1100 μM for EDDP and 20 and 1000 μM for EMDP formation. Intestinal microsomal LAAM and nor-LAAM N -demethylation also exhibited hyperbolic kinetics and biphasic Eadie-Hofstee plots. K m values were 21 and 980 μM for nor-LAAM from LAAM and 18 and 1200 μM for dinor-LAAM from nor-LAAM. Troleandomycin and ketoconazole inhibited N -demethylation by >70%. LAAM and nor-LAAM metabolism by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; K m values were 8 and 1300 μM, 6 and 950 μM, respectively. Predicted in vivo intestinal extraction of methadone and LAAM is 21 and 33%, respectively. We conclude that methadone, LAAM, and nor-LAAM are metabolized by human intestinal microsomes; CYP3A4 is the predominant cytochrome P450 isoform; CYP3A4-catalyzed methadone, LAAM, and nor-LAAM metabolism is characterized by noncooperative, multisite kinetics; and intestinal metabolism may contribute to presystemic methadone inactivation and LAAM bioactivation.

Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation.

Metabolism of acetylmethadol. Sensitive assay for noracetylmethadol and the identification of a new active metabolite

Synthesis of acronycine

A series of 5-substituted and 2,5-disubstituted 1,3-dioxanes was prepared and evaluated for analgesic activity in mice and rats. Some of the compounds possessed significant analgesic effects; their structure-activity relationships and chemistry are discussed. These compounds represent a unique series of analgesic agents.

Various 5-substituted and 2,5-disubstituted 1,3-dioxanes, a new class of analgesic agents.

The primary amine metabolites of alpha-(plus or minus)- alpha-(minus)-acetylmethadol were synthesized. A neutral permanganate oxidation of noracetylmethadol gave a nitroalkane. This unusual oxidation product was readily converted to the primary amine metabolite of acetylmethadol.

Albert Pohland

Papers

Metabolism of acetylmethadol. Sensitive assay for noracetylmethadol and the identification of a new active metabolite

Synthesis of acronycine

Various 5-substituted and 2,5-disubstituted 1,3-dioxanes, a new class of analgesic agents.

Synthesis of a new metabolite of acetylmethadol.

Verfahren zur Herstellung von Acronycin und verwandten Verbindungen