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J Pharmacol Exp Ther. 2018 Nov;367(2):222-233. doi: 10.1124/jpet.118.250902. Epub 2018 Aug 27.

Interactions between Cocaine and the Putative Allosteric Dopamine Transporter Ligand SRI-31142.

Author information

1
Departments of Pharmacology and Toxicology (M.J.M., M.L.B., K.C.F., A.R.J., S.S.N.) and Physiology and Biophysics (J.M.E., T.W.E.S.), Virginia Commonwealth University, Richmond, Virginia; and Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama (S.A., S.K.S.).
2
Departments of Pharmacology and Toxicology (M.J.M., M.L.B., K.C.F., A.R.J., S.S.N.) and Physiology and Biophysics (J.M.E., T.W.E.S.), Virginia Commonwealth University, Richmond, Virginia; and Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, Alabama (S.A., S.K.S.) sidney.negus@vcuhealth.org.

Abstract

Drugs that inhibit the dopamine (DA) transporter (DAT) include both therapeutic agents and abused drugs. Recent studies identified a novel series of putative allosteric DAT inhibitors, but the in vivo effects of these compounds are unknown. This study examined the abuse-related behavioral and neurochemical effects produced in rats by SRI-31142 [2-(7-methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine], one compound from this series. In behavioral studies, intracranial self-stimulation (ICSS) was used to compare the effects produced by SRI-31142, the abused and nonselective DAT inhibitor cocaine, and the selective DAT inhibitor GBR-12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine]. In neurochemical studies, in vivo microdialysis was used to compare the effects of SRI-31142 and cocaine on levels of DA and serotonin in nucleus accumbens (NAc). The effects of SRI-31142 in combination with cocaine were also examined in both procedures. In contrast to cocaine and GBR-12935, SRI-31142 failed to produce abuse-related increases in ICSS or NAc DA; instead, SRI-31142 only decreased ICSS and NAc DA at a dose that was also sufficient to block cocaine-induced increases in ICSS and NAc DA. Pharmacokinetic studies suggested low but adequate brain penetration of SRI-31142, in vitro binding studies failed to identify likely non-DAT targets, and in vitro functional assays failed to confirm DA uptake inhibition in an assay of DAT-mediated fluorescent signals in live cells. These results indicate that SRI-31142 does not produce cocaine-like abuse-related effects in rats. SRI-31142 may have utility to block cocaine effects and may warrant further study as a candidate pharmacotherapy; however, the role of DAT in mediating these effects is unclear, and side effects may be a limiting factor.

PMID:
30150482
PMCID:
PMC6170971
[Available on 2019-11-01]
DOI:
10.1124/jpet.118.250902

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