- Significant progress was made on this project, and several papers were published. In one notable article, we describe the discovery of partial transporter substrates which have limited ability to release monoamine transmitters. Such compounds could have utility for treating addiction and ADHD, without causing typical stimulant-associated adverse effects (i.e., abuse liability). Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters. (2012) J. Pharmacol. Exp. Ther. 341:251-261. Several compounds have been identified that display low-efficacy, "partial substrate" activity. Here, we tested the hypothesis that the mechanism of this effect is a slower rate of induced neurotransmitter efflux than that produced by full substrates. Biogenic amine transporter release assays were carried out in rat brain synaptosomes and followed published procedures. (3)H1-methyl-4-phenylpyridinium (MPP(+)) was used to assess release from dopamine (DA) and norepinephrine nerve terminals, whereas (3)H5-hydroxytryptamine (5-HT) was used to assess release from 5-HT nerve terminals. A detailed time-course evaluation of DA transporter (DAT)-mediated efflux was conducted by measuring the efflux of (3)HMPP(+) after the addition of various test compounds. In vivo microdialysis experiments compared the effects of the full substrates ()-1-(2-naphthyl)propan-2-amine (PAL-287) and (S)-N-methyl-1-(2-naphthyl)propan-2-amine (PAL-1046), to that of a partial DAT/5-HT transporter substrate (S)-N-ethyl-1-(2-naphthyl)propan-2-amine (PAL-1045) on extracellular DA and 5-HT in the nucleus accumbens of the rat. The in vitro release assays demonstrated that partial substrate activity occurs at all three transporters. In the DAT efflux experiments, D-amphetamine (full substrate) promoted a fast efflux (K1 = 0.24 min(-1)) and a slow efflux (K2 = 0.008 min(-1)). For the partial DAT substrates, K1 = 0.04 min(-1), and K2 approximated zero. The in vivo microdialysis experiments showed that the partial substrate (PAL-1045) was much less effective in elevating extracellular DA and 5-HT than the comparator full substrates. We conclude that low-efficacy partial DAT substrates promote efflux at a slower rate than full substrates, and "partiality" reflects the ultra-slow K2 constant, which functionally limits the ability of these compounds to increase extracellular DA. We speculate that partial biogenic amine transporter substrates bind to the transporter but are less effective in inducing conformational changes required for reverse transport activity.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$609,062
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
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Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S et al. (2016) Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters. Mol Pharmacol 89:165-75
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Blough, Bruce E; Landavazo, Antonio; Partilla, John S et al. (2014) Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics. ACS Med Chem Lett 5:623-7
Blough, Bruce E; Landavazo, Antonio; Decker, Ann M et al. (2014) Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology (Berl) 231:4135-44
Cozzi, Nicholas V; Brandt, Simon D; Daley, Paul F et al. (2013) Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs. Eur J Pharmacol 699:180-7
Theberge, Florence R; Li, Xuan; Kambhampati, Sarita et al. (2013) Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving. Biol Psychiatry 73:729-37

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