MAILMAN RESEARCH CENTER

Bio-Organic and Natural Products Research Laboratory

The Bio-Organic and
Natural Products Researchers
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This medication development program focuses on the discovery and development of pharmacotherapies for the treatment of alcohol and drug abuse and provides analytical chemistry support for clinical studies at McLean Hospital.

Over the past decade, research on possible pharmacotherapies for the treatment of alcohol and drug abuse has burgeoned. For instance, naltrexone, an opioid receptor antagonist, was recently approved in the United States for the treatment of alcohol-dependent patients. However, naltrexone can produce liver toxicity, and compliance has been a problem. Therefore, a greater research effort is needed to develop agents with less side-effect liability.

Our strategy is to investigate Chinese herbal remedies traditionally used for the treatment of alcohol and drug abuse. As evidenced in our study, puerarin, an isoflavone-C-glycoside isolated from Pueraria lobata, reduces alcohol drinking in alcohol preferring rats and monkeys and shows significant improvement of the withdrawal syndrome in alcoholic rats models. The naturally occurring progesterone metabolite allopregnanolone, a potent modulator of the GABAA receptor, has profound effects on stress, anxiety, and alcohol- and drug-seeking behavior.

Preliminary results from our laboratories show that certain synthetic analogs of allopregnanolone with improved half-life can stimulate Cl- uptake in synaptoneurosomes, protect against bicuculline-induced seizures in alcohol dependent rats, and reduce alcohol intake in alcohol preferring rats. Collectively, it appears that this class of compound might indeed yield some of the most potent GABAA-active agents with clinical significance. Other natural products, such as huperzine A, a potent acetylcholinesterase inhibitor isolated from the Chinese herb Huperzia serrata, are being evaluated for Alzheimer's disease.

Keywords

Isoflavone-C-glycosides, neurosteroids, anti-craving agents, alcohol drinking, pharmacokinetics, drug metabolism, pharmacotherapies.

Grant Support

NIAAA: RO1 AA12720-03, Novel Neurosteroids for Alcohol Related Conditions (Lee)
NIAAA: N44AA02006-02, Development of Puerarin to Reduce Alcohol Drinking (Lee)
NIAAA: RO1 AA10536, Isoflavone Treatment for Alcohol Abuse (SEL)
NCI: RO1 CA81001-03, SAR of Novel Topo-1 Inhibitor Against Prostate Cancer (Lee)
NCCAM: P50 AT00084-01, Alternative Pharmacotherapies for Immune Mediated Arthritis (Berman)
NCCAM: R42 AT00766-01, Development of Standardized Milk Thistle Product (Lee).

Program Director

David Yue-Wei Lee, Ph.D.

Program Personnel

Contact Person

Ann Miller, Administrative Assistant
Tel. (617) 855-2060
Fax (617) 855-3479

Representative Publications

Overstreet DH, Lee YW, Rezuani AH, Pei YH, Criswell HE, Janowsky DS: Suppression of Alcohol Intake following Administration of the Chinese Herbal Medicine (NPI-028) and Its Derivatives. Alcoholism: Clinical and Experimental Research 1996; 20 (2): 221-227.
Lin RC, Guthrie S, Xie C-Y, Mai K, Lee DY-W, Lumeng L, Li T-K: Isoflavonoid Compounds Extracted From Pueraria Lobata Suppress Alcohol Preference In A Pharmacogenetic Rat Model of Alcoholism. Alcoholism: Clinical and Experimental Research 1996; 20 (4): 659-663.
Lee YW, Overstreet DH,. Rezvani AH: Naturally Occurring Suppressors for Alcohol Intake, Alcohol Clin. Exp. Res. 1996; Vol 20: 231A-235A.
Cook CE, Jump JM, Zhang PS, Stephens JR, Lee YW, Fail PA, Anderson SA: Exceptionally Potent Antispermatogenic Compounds From 8-Halogenation Of (4ars, 5sr, 9brs) Hexahydroindeno [1,2-C] Pyridine, J. Med. Chem., 1997, 40 (14), 2111-2112.
Overstreet DH, Lee YW, Chen YT, Rezvani AH: The Chinese Herbal Medicine Npi-028 Suppresses Alcohol Intake In Alcohol-Preferring Rats And Monkeys Without Inducing Taste Aversion, J. of Perfusion, 1998; 11: 381-389.
Lee, YW., Cross-Axis Countercurrent Chromatography: A versatile technique for biotech purification, Chromatographic Science Series, 1999; 82: 149-169.
Cook, CE., Raji P., Lee, YW., Kepler, JA., Effect of a 17a-(3-hydroxypropopyl)-17 fl-acetyl substituted pattern on the glucocorticord and progestin receptor binding. Organic Letter, 2001; 3(7), 1013-1016.
Keyler, DE., Baker, JI., Lee, YW., Overstreet, DH., Boucher, TA., Lenz, SK., A toxicity study of the Chinese herbal medicine NPI-028 in rats. Submitted to the journal of Altenative Medicine, August, 2001.
Keyler, D.E., Baker, J.I., Lee, Y.W., Overstreet, D.H., Boucher, T.A., Lenz, S.K.: A Toxicity Study of the Chinese Herbal Medicine NPI-028 in Rats. Journal of Alternative and Complementary Medicine, 8, 175-183, 2002.
Overstreet, D. H., Ma, Z. Z., Lee, Y. W., Herbal Remedies for Alcoholism: Promises and Possible Pitfalls. Journal of Alcoholism: Clinical and Experimental Research, 27(2):177-85, 2003. The Isoflavone NPI-031G Acutely Reduces Alcohol Intake in Alcohol-Preferring Rats and Monkeys, Journal of Alcoholism: Clinical and Experimental Research, Submitted in September 2002.