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

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.