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Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2016 Apr; Vol. 357 (1), pp. 24-35. Date of Electronic Publication: 2016 Jan 26. - Publication Year :
- 2016
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Abstract
- Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.<br /> (U.S. Government work not protected by U.S. copyright.)
- Subjects :
- Adenine chemistry
Cocaine analogs & derivatives
Cocaine antagonists & inhibitors
Cocaine metabolism
Cocaine pharmacology
Dopamine Plasma Membrane Transport Proteins drug effects
Dopamine Plasma Membrane Transport Proteins metabolism
HEK293 Cells
Humans
Norepinephrine Plasma Membrane Transport Proteins drug effects
Norepinephrine Plasma Membrane Transport Proteins metabolism
Protein Binding drug effects
Serotonin Plasma Membrane Transport Proteins drug effects
Serotonin Plasma Membrane Transport Proteins metabolism
Sodium metabolism
Structure-Activity Relationship
Vesicular Monoamine Transport Proteins metabolism
Adenine analogs & derivatives
Adenine pharmacology
Dopamine metabolism
Norepinephrine metabolism
Nucleosides chemistry
Nucleosides pharmacology
Symporters drug effects
Symporters metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 357
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 26813929
- Full Text :
- https://doi.org/10.1124/jpet.115.229666