A Hybrid Indoloquinolizidine Peptide as Allosteric Modulator of Dopamine D-1 Receptors

Aroa Soriano, Marc Vendrell, Sergio Gonzalez, Josefa Mallol, Fernando Albericio, Miriam Royo, Carmen Lluis, Enric I. Canela*, Rafael Franco, Antoni Cortes, Vicent Casado

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The indoloquinolizidine-peptide 28 [(3S,12bR)-N-((S)-1-((S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-(4-fluorophenyl)-1-oxopropan-2ylamino)- 4-cyclohexyl-1-oxobutan-2-yl)-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a] quinolizine-3-carboxamide], a trans-indoloquinolizidine-peptide hybrid obtained by a combinatorial approach, behaved as an orthosteric ligand of all dopamine D-2 like receptors (D-2, D-3, and D-4) and dopamine D-5 receptors, but as a negative allosteric modulator of agonist and antagonist binding to striatal dopamine D-1 receptors. Indoloquinolizidine-peptide 28 induced a concentration-dependent hyperbolic increase in the antagonist apparent equilibrium dissociation constant values and altered the dissociation kinetics of dopamine D-1 receptor antagonists. The negative allosteric modulation was also found when agonist binding to D-1 receptors was assayed. Indoloquinolizidine-peptide 28 was a weak ago-allosteric modulator but markedly led to a decreased potency without decreasing the maximum partial/full agonist-mediated effect on cAMP levels. Compounds able to decrease the potency while preserving the efficacy of D-1 receptor agonists are promising for exploration in psychotic pathologies.

Original languageEnglish
Pages (from-to)876-885
Number of pages10
JournalJournal of pharmacology and experimental therapeutics
Volume332
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • PROTEIN-COUPLED RECEPTORS
  • WORKING-MEMORY
  • CELL-MEMBRANE
  • BINDING
  • AGONISTS
  • SCHIZOPHRENIA
  • PHARMACOLOGY
  • ANTAGONISTS
  • HETEROMERS
  • MECHANISMS

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