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Bioorg Med Chem. 2017 Apr 1;25(7):2260-2265. doi: 10.1016/j.bmc.2017.02.052. Epub 2017 Feb 27.

Role of the sugar moiety on the opioid receptor binding and conformation of a series of enkephalin neoglycopeptides.

Author information

1
Instituto de Química Avanzada de Cataluña (IQAC-CSIC), E-08034 Barcelona, Spain.
2
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Instituto de Neurociencias de Castilla y León (INCyL), University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), E-37007 Salamanca, Spain.
3
UCIBIO, REQUIMTE Faculdade Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
4
Department of Cell Biology and Pathology, Faculty of Medicine, Instituto de Neurociencias de Castilla y León (INCyL), University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), E-37007 Salamanca, Spain.
5
CIC bioGUNE, Bizkaia Technological Park, E-48160 Derio, Spain.
6
CIC bioGUNE, Bizkaia Technological Park, E-48160 Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao E-48013, Spain; Department of Organic Chemistry II, Faculty of Science and Technology, University of the Basque Country, EHU/UPV, E-48940 Leioa, Bizkaia, Spain.
7
Instituto de Química Avanzada de Cataluña (IQAC-CSIC), E-08034 Barcelona, Spain. Electronic address: gregorio.valencia@iqac.csic.es.

Abstract

Glycosylation by simple sugars is a drug discovery alternative that has been explored with varying success for enhancing the potency and bioavailability of opioid peptides. Long ago we described two O-glycosides having either β-Glucose and β-Galactose of (d-Met2, Pro5)-enkephalinamide showing one of the highest antinociceptive activities known. Here, we report the resynthesis of these two analogs and the preparation of three novel neoglycopeptide derivatives (α-Mannose, β-Lactose and β-Cellobiose). Binding studies to cloned zebrafish opioid receptors showed very small differences of affinity between the parent compound and the five glycopeptides thus suggesting that the nature of the carbohydrate moiety plays a minor role in determining the binding mode. Indeed, NMR conformational studies, combined with molecular mechanics calculations, indicated that all glycopeptides present the same major conformation either in solution or membrane-like environment. The evidences provided here highlight the relevance for in vivo activity of the conjugating bond between the peptide and sugar moieties in opioid glycopeptides.

KEYWORDS:

Enkephalin-related; Glycosylation; Neoglycopeptides; Neuropeptide; Opioid receptors; Pharmacology

PMID:
28284867
DOI:
10.1016/j.bmc.2017.02.052
[Indexed for MEDLINE]

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