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 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.
Footnotes
This work was supported by the Spanish Ministerio de Ciencia y Tecnología [Grants SAF2008-00146, SAF2009-07276] (to E.I.C. and R.F., respectively); and Fundació La Marató de TV3 [Grant 060110 ] (to E.I.C.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158824.
↵
The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.-
ABBREVIATIONS:
- GPCR
- G-protein-coupled receptor
- IP28
- 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 (C40H51FN6O4)
- SCH 23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- SKF 38393
- 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
- SKF 81297
- (±)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide
- A77636
- (1R,3S)-3-(1′-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran
- SKF 83566
- 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benza zepin-7-ol hydrobromide
- YM-09151–2
- cis-5-chloro-2-methoxy-4(methylamine)-N-[2-methyl-1-(phenylmethyl)-3-pyrrolidinyl]benzamide
- HBSS
- Hank's balanced salt solution
- FRT
- Flp recombination target
- HEK
- human embryonic kidney.
- Received July 13, 2009.
- Accepted December 17, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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A Hybrid Indoloquinolizidine Peptide as Allosteric Modulator of Dopamine D1 Receptors
