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NEUROPHARMACOLOGY

The Triple Uptake Inhibitor (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0] Hexane Hydrochloride (DOV 21947) Reduces Body Weight and Plasma Triglycerides in Rodent Models of Diet-Induced Obesity

Department of Preclinical Pharmacology, DOV Pharmaceutical, Inc., Somerset, New Jersey (J.P.T., P.A.K., P.S., A.S.B.); Department of Psychiatry, Obesity Research Center and Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio (D.P.-T., M.H.T.); and Departments of Metabolic Disorders (A.F., R.Z.C., T.M.F.) and Pharmacology (D.S.S., A.S., L.S.), Merck Research Laboratories, Rahway, New Jersey

Selective inhibitors of biogenic amine (e.g., serotonin, norepinephrine, and dopamine) uptake exhibit varying degrees of safety and efficacy as antiobesity agents. Moreover, preclinical findings suggest that the combined inhibition of monoamine neurotransmitter transporters synergistically enhances antiobesity activity. (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride (DOV 21947) inhibits norepinephrine, 5-hydroxytryptamine, and dopamine uptake, and it reduces body weight in rodent models of diet-induced obesity (DIO). DIO rats treated orally with DOV 21947 for 1 to 24 days showed significantly lower body weights than vehicle-treated DIO rats. The decrease in body weight resulted specifically from a loss of retroperitoneal and mesenteric depots of white adipose tissue. DOV 21947 also reduced daily food intake in DIO rats, but consumption returned to control levels after 11 days of treatment. With the exception of a decrease in triglyceride levels, blood chemistry was unaltered after 24 days of DOV 21947 treatments. DOV 21947 had no effect on motor activity. Although DOV 21947 increased respiratory rate and decreased the tidal volume of normal rats, it did not alter the minute volume. In addition, DOV 21947 did not significantly affect blood pressure, heart rate, electrocardiographic indices or body temperature in telemeterized dogs. However, it caused a sustained, but reversible reduction in the rate of body weight gain for as long as 6 months in normal rats, and for up to 1 year in normal dogs. In summary, DOV 21947 is effective in causing a sustained and selective reduction in fat content and triglyceride levels in animal models of obesity without significantly altering vital organ function.

Address correspondence to: Dr. Anthony S. Basile, DOV Pharmaceutical, Inc., 150 Pierce St., Somerset, NJ 08873-4185. E-mail: abasile{at}dovpharm.com

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