Therapeutic Potential of Monoamine Transporter Substrates

Richard B. Rothman; Michael H. Baumann

doi:10.2174/156802606778249766

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Abstract

Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.

Keywords: Transporters, dopamine, serotonin, release, amphetamine, PAL-287

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Current Topics in Medicinal Chemistry

Title: Therapeutic Potential of Monoamine Transporter Substrates

Volume: 6 Issue: 17

Author(s): Richard B. Rothman and Michael H. Baumann

Affiliation:

Keywords: Transporters, dopamine, serotonin, release, amphetamine, PAL-287

Abstract: Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (α-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions.

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Cite this article as:

Rothman B. Richard and Baumann H. Michael, Therapeutic Potential of Monoamine Transporter Substrates, Current Topics in Medicinal Chemistry 2006; 6 (17) . https://dx.doi.org/10.2174/156802606778249766

DOI https://dx.doi.org/10.2174/156802606778249766	Print ISSN 1568-0266
Publisher Name Bentham Science Publishers	Online ISSN 1873-4294

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