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 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.
Soriano
Aroa
A
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
Vendrell
Marc
M
Gonzalez
Sergio
S
Mallol
Josefa
J
Albericio
Fernando
F
Royo
Miriam
M
Lluís
Carmen
C
Canela
Enric I
EI
Franco
Rafael
R
Cortés
Antoni
A
Casadó
Vicent
V
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
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