A hybrid indoloquinolizidine peptide as allosteric modulator of dopamine D1 receptors

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 transindoloquinolizidine-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.