RT Journal Article
SR Electronic
T1 A Hybrid Indoloquinolizidine Peptide as Allosteric Modulator of Dopamine D<sub>1</sub> Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 876
OP 885
DO 10.1124/jpet.109.158824
VO 332
IS 3
A1 Aroa Soriano
A1 Marc Vendrell
A1 Sergio Gonzalez
A1 Josefa Mallol
A1 Fernando Albericio
A1 Miriam Royo
A1 Carmen Lluís
A1 Enric I. Canela
A1 Rafael Franco
A1 Antoni Cortés
A1 Vicent Casadó
YR 2010
UL http://jpet.aspetjournals.org/content/332/3/876.abstract
AB 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 D2-like receptors (D2, D3, and D4) and dopamine D5 receptors, but as a negative allosteric modulator of agonist and antagonist binding to striatal dopamine D1 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 D1 receptor antagonists. The negative allosteric modulation was also found when agonist binding to D1 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 D1 receptor agonists are promising for exploration in psychotic pathologies.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics