Rigid adenine nucleoside derivatives as novel modulators of the human sodium symporters for dopamine and norepinephrine

Aaron Janowsky, Dilip K. Tosh, Amy J. Eshleman, Kenneth A. Jacobson

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 [125I] 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 [3H]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 N6-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 [125I]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.

Original languageEnglish (US)
Pages (from-to)24-35
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume357
Issue number1
DOIs
StatePublished - Apr 1 2016

Fingerprint

Symporters
Serotonin Plasma Membrane Transport Proteins
Adenine
Nucleosides
Norepinephrine Plasma Membrane Transport Proteins
Dopamine
Norepinephrine
Sodium
Mazindol
Dopamine Uptake Inhibitors
Purinergic P1 Receptor Agonists
Tropanes
Ligands
Dopamine Plasma Membrane Transport Proteins
Purinergic P1 Receptors
Ribose
Structure-Activity Relationship
Cocaine
Adenosine
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Rigid adenine nucleoside derivatives as novel modulators of the human sodium symporters for dopamine and norepinephrine. / Janowsky, Aaron; Tosh, Dilip K.; Eshleman, Amy J.; Jacobson, Kenneth A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 357, No. 1, 01.04.2016, p. 24-35.

Research output: Contribution to journalArticle

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