Chemical modifications to alter monoamine releasing activity of phenmetrazine analogs as potential treatments of stimulant addiction
Namjoshi, O. A., Decker, A. M., Landavazo, A., Partilla, J. S., Baumann, M. H., Rothman, R. B., & Blough, B. E. (2015). Chemical modifications to alter monoamine releasing activity of phenmetrazine analogs as potential treatments of stimulant addiction. Drug and Alcohol Dependence, 146, e48. https://doi.org/10.1016/j.drugalcdep.2014.09.502
Abstracts from the 2014 annual meeting of the College on Problems of Drug Dependence
Aims: According to the dual deficit model of stimulant addiction, dopamine (DA) and serotonin (5-HT) deficits contribute to withdrawal, drug craving, and relapse. Dual DA/5-HT releasers would provide the necessary stimulant-like properties via DA release, and its ability to release 5-HT would reduce its abuse liability. Previous data with universal releaser PAL287 suggest that 5-HT elevations counteract DA's reinforcing effects. Similarly (+)-phenmetrazine, a potent DA releaser with weak 5-HT releasing activity, selectively suppresses cocaine vs food maintained responding. Hence the aim was to synthesize and evaluate analogs of phenmetrazine to understand the structural requirements for DA and 5-HT releasing activity and to afford a superior dual DA/5-HT releasing agent for treatment of stimulant addiction.
Methods: Electron-withdrawing, donating and bulkier substituents on the phenyl ring of phenmetrazine were incorporated as racemic as well as enantiopure forms. Positional isomers of the alkyl substituent on the morpholine ring were also synthesized. These ligands were evaluated for DA/5-HT release ability. Standard transporter uptake inhibition and superfusion release assays using synaptosomes prepared from rat brain were used.
Results: In this study 3′-substituted compounds were DA releasers while some 4′-substituted compounds were DA reuptake inhibitors. Importantly 3′-chloro analog (PAL594) of (+)-phenmetrazine afforded DA as well as 5-HT releasing activity at EC50 values of 27 nM and 301 nM, respectively. Two compounds, PAL730 and PAL738, are more potent DA/5-HT releasers than phenmetrazine, with PAL738 exhibiting DA and 5-HT releasing activity at EC50 values of 58 nM and 23 nM, respectively.
Conclusions: Results contribute to the evidence supporting the potential utility of monoamine releasers as candidate treatments for stimulant addictions.
Financial support: Supported by NIDA grant DA012970 to BEB.