title: A hybrid indoloquinolizidine peptide as allosteric modulator of dopamine D1 receptors.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Aroa
authors.initials: A
authors.lastname: Soriano
authors.forename: Marc
authors.initials: M
authors.lastname: Vendrell
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonzalez
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
authors.forename: Carmen
authors.initials: C
authors.lastname: Lluís
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000494:Allosteric Regulation; D001552:Benzazepines / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D054333:Drug Partial Agonism; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000494:pharmacology*; D054837:Quinolizidines / Q000494:pharmacology*; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D001552:Benzazepines; D008024:Ligands; C548546:N-(1-(1-(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; D009842:Oligopeptides; D054837:Quinolizidines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C534628:SCH 23390; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C067113:SK&F 81297; D000242:Cyclic AMP