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Eur J Med Chem. 2015 Jun 5;97:173-80. doi: 10.1016/j.ejmech.2015.04.052. Epub 2015 Apr 28.

A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D(1) and D(2) dopamine receptors.

Author information

1
Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, 08028 Barcelona, Spain.
2
Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, 08028 Barcelona, Spain; MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ Edinburgh, United Kingdom. Electronic address: mvendrel@staffmail.ed.ac.uk.
3
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas. (CIBERNED), Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
4
Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
5
CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, 08028 Barcelona, Spain; Institute for Research in Biomedicine, 08028 Barcelona, Spain.
6
Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, 08028 Barcelona, Spain; CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, 08028 Barcelona, Spain. Electronic address: mroyo@pcb.ub.cat.

Abstract

Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D1R and D2R with high affinity could restore the effects of dopamine depletion and enhance motor activation on degenerated nigrostriatal dopaminergic systems. We have directed our research towards the synthesis and characterisation of heterocycle-peptide hybrids based on the indolo[2,3-a]quinolizidine core. This privileged structure is a water-soluble and synthetically accessible scaffold with affinity for diverse GPCRs. Herein we have prepared a solid-phase combinatorial library of 80 indoloquinolizidine-peptides to identify compounds with enhanced binding affinity at D2R, a receptor that is crucial to re-establish activity on dopamine-depleted degenerated GABAergic neurons. We applied computational tools and high-throughput screening assays to identify 9a{1,3,3} as a ligand for dopamine receptors with nanomolar affinity and agonist activity at D2R. Our results validate the application of indoloquinolizidine-peptide combinatorial libraries to fine-tune the pharmacological profiles of multiple ligands at D1 and D2 dopamine receptors.

KEYWORDS:

GPCRs; Heterocycles; Neurodegenerative diseases; Privileged scaffolds; Solid-phase synthesis

PMID:
25969169
DOI:
10.1016/j.ejmech.2015.04.052
[Indexed for MEDLINE]
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