This is a Phase I Small Business Technology Transfer (STTR) grant application in response to Pharmacologic Agents and Drugs for Mental Disorders (STTR [R41/R42]). The goal of this proposal of 1 year's length is to identify a potential antidepressant with a novel mechanism of action. This novel mechanism of action is the blockade of transporters for the neurotransmitters norepinephrine (NET), serotonin (SERT), and dopamine (DAT). Compelling evidence from the clinical literature suggests that remission rates are higher with antidepressants that block re-uptake of both norepinephrine and serotonin. While low dopamine has been implicated in the pathophysiology of depression, particularly the feature of anhedonia, there is currently no antidepressant that potently blocks all 3 transporters. It is likely that a drug that blocks all 3 transporters would be a very efficacious and possibly, a faster-acting antidepressant. This work is made possible by our synthesis of analogs of the antidepressant venlafaxine. Unlike venlafaxine, our compounds are triple re-uptake inhibitors. The proposed preclinical studies will be done on 3 pairs of enantiomers, which we have resolved from the racemic compounds called PRC006, PRC011, and PRC012. All these racemic mixtures are active in preclinical tests predictive of antidepressant activity. A U.S. Patent has been issued on these compounds, with the Principal Investigator (E. Richelson) and Consultant (P. Carlier) of this grant application among the co-inventors (U.S. Patent #6,069,177, May 30, 2000).
The Specific Aims of this grant application are to synthesize 200 mg of each compound and then test each in vitro (binding activity at human transporters for norepinephrine, serotonin, and dopamine expressed in cell lines; inhibitory activity at a human cardiac ion channel, called hERG, potent activity at which would preclude further development; and inhibitory activity at cytochrome P450 enzymes, which are involved in drug metabolism. With these data, we will be able to accept or reject a compound for the next Specific Aim, which is the preclinical tests predictive of antidepressant effects in humans. In addition, because DAT transporter blockade has some liability for abuse, for the last Specific Aim, we plan to test our selected compound in preclinical models that relate to abuse liability. These models are 1) behavioral sensitization; 2) withdrawal signs with cessation of repeated treatment; and 3) reinforcement in an operant-conditioning paradigm, in laboratory animals are trained to press a lever to self-infuse the drug. The most potent compound (based on the in vitro and in vivo data) will be chosen to take into preclinical toxicology testing.? ? ? ? ? ?
