title: A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D(1) and D(2) dopamine receptors.
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.
authors.affiliation: Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: Molero
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Vendrell
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Zachmann
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.affiliation: 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.
authors.forename: Carme
authors.initials: C
authors.lastname: Lluis
authors.affiliation: 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.
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, 08028 Barcelona, Spain; Institute for Research in Biomedicine, 08028 Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Albericio
authors.affiliation: 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.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: 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.
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D003412:Cricetulus; D015195:Drug Design; D007211:Indoles; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054837:Quinolizidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D010455:Peptides; D054837:Quinolizidines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D054852:Small Molecule Libraries
keywords: GPCRs; Heterocycles; Neurodegenerative diseases; Privileged scaffolds; Solid-phase synthesis