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

作者：Molero Anabel; Vendrell Marc^*; Bonaventura Jordi; Zachmann Julian; Lopez Laura; Pardo Leonardo; Lluis Carme; Cortes Antoni; Albericio Fernando; Casado Vicent; Royo Miriam

来源：European Journal of Medicinal Chemistry, 2015, 97: 173-180.

DOI：10.1016/j.ejmech.2015.04.052

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

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 D-1 and D-2 dopamine receptors.

• 出版日期2015-6-5