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Novel CNS‐Permeant PKC Inhibitor And Tamoxifen Analog Reduces Amphetamine Neurochemical And Behavioral Effects
Author(s) -
Carpenter Colleen,
Mikelman Sarah,
Gnegy Margaret
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.768.16
Subject(s) - amphetamine , neurochemical , chemistry , pharmacology , dopamine , protein kinase c , tamoxifen , endocrinology , medicine , signal transduction , biochemistry , cancer , breast cancer
Amphetamines (AMPHs) are highly addictive and their overuse carries serious health risks. The rewarding and reinforcing effects of AMPH use are linked to its ability to elicit an increase in extracellular dopamine levels in the brain via PKC activation. We have shown that PKC inhibition significantly reduces AMPH action; therefore PKC inhibitors could fill the unmet need for effective treatments against AMPH abuse. The selective estrogen receptor modulator tamoxifen is currently the only available CNS‐permeant PKC inhibitor. We are using tamoxifen as a scaffold to produce a library of analogs that have increased selectivity for PKC inhibition compared to estrogen receptor binding. Our aim is to evaluate the effectiveness of our lead compounds in reducing AMPH neurochemical and behavioral effects. We tested the PKC inhibition and estrogen binding affinities of the tamoxifen analogs. Additionally, we monitored the effects of the analogs on AMPH‐stimulated dopamine efflux in striatal synaptosomes (using suprafusion) and AMPH‐stimulated locomotion. Through our structure‐activity modeling we have generated a compound, 8‐093c, which inhibits PKC activity with an IC 50 of 0.14 μM but does not bind estrogen receptor α at concentrations up to 10 μM. Suprafusion of mouse and rat striatal synaptosomes with 3 μM 8‐093c significantly reduces dopamine efflux stimulated by 10 μM AMPH. Similarly, administration of 3 mg/kg i.p. 8‐093c reduces locomotion stimulated by 3 mg/kg i.p. AMPH by 40% in mice. The novel CNS‐permeant PKC inhibitor, 8‐093c, significantly reduces in‐vivo AMPH effects and AMPH‐induced dopamine efflux. This further supports the notion that PKC is a druggable target for the treatment of AMPH abuse. Source of funding: NIH grant 1R01 DA11697‐12.