A solid-phase combinatorial approach for indoloquinolizidine-peptides with high affinity at D1 and D2 dopamine receptors

Abstract

Abstract.Ligands acting at multiple dopamine receptors hold potential as therapeutic agents for a number of neurodegenerative disorders. Specifically, compounds able to bind at D 1 R and D 2 R 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 D 2 R, 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 D 2 R. 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.

Conjugation as a Tool in Therapeutics: Role of Amino Acids/Peptides-Bioactive (Including Heterocycles) Hybrid Molecules in Treating Infectious Diseases

“…Among the tripeptides containing Phe(4-F), Phe(3,4-F 2 ), Trp and Tyr, there was an increase in activity with K D value of 1.3 ± 0.2 µM and 0.19 ± 0.06 µM for D 1 R and D 2 R, which may be due to increased H-bonding property. The compounds containing positively charged amino acids at the C-terminal residue enhanced the affinity at both dopamine receptors and compounds with trans-configuration at the indoloquinolizidine core, thus prominently enhancing the selectivity towards D 2 R [ 147 ].…”

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

“…Therefore, the accomplishment of at least two out of three criteria is required for the acceptance of a GPCR heteromer (Jonas and Hanyaloglu, 2017). The main strategies to target GPCR heteromers are the generation of selective compounds, which exhibit higher efficacy in tissues from wild type animals or in cells expressing both receptors than in knock-out animals tissues or in cell only expressing the individual receptors (Akgün et al, 2013; Gomes et al, 2013a; Molero et al, 2015; Nimczick and Decker, 2015; Peterson et al, 2017). Likewise, the use of membrane-permeable peptides that target the dimerization interface or heteromer-selective antibodies that can recognize an epitope in the heteromer but not in the individual protomers, have been most useful to detect GPCRs heteromers in vivo (Gupta et al, 2010; He et al, 2011; Viñals et al, 2015; Gomes et al, 2016a; Moreno et al, 2017; Jacobs et al, 2018).…”

Fluorescent cyclic peptides for cell imaging

“…Their lability to proteolytic enzymes—particularly in diseased tissue where proteases may be abundant—has prompted the development of alternative chemical structures that can retain the molecular recognition properties of the peptides while displaying enhanced chemical stability. [ 2,3 ] Some of these alternative designs include the incorporation of unnatural amino acids, such as functionalised or D‐amino acids, [ 4–8 ] into the peptide sequence as well as the cyclisation of linear peptides. Cyclic peptides are ubiquitously found in natural products, from complex macrocycles to small cyclodipeptides.…”