Dissemin is shutting down on January 1st, 2025

Published in

American Society for Pharmacology and Experimental Therapeutics (ASPET), The Journal of Pharmacology and Experimental Therapeutics, 3(332), p. 876-885, 2009

DOI: 10.1124/jpet.109.158824

Links

Tools

Export citation

Search in Google Scholar

A Hybrid Indoloquinolizidine Peptide as Allosteric Modulator of Dopamine D<sub>1</sub> Receptors

This paper is available in a repository.
This paper is available in a repository.

Full text: Download

Green circle
Preprint: archiving allowed
Red circle
Postprint: archiving forbidden
Red circle
Published version: archiving forbidden
Data provided by SHERPA/RoMEO

Abstract

The indoloquinolizidine-peptide 28 [(3S,12bR)-N-((S)-1-((S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-(4-fluorophenyl)-1-oxopropan-2-ylamino)-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.