Role of the sugar moiety on the opioid receptor binding and conformation of a series of enkephalin neoglycopeptides. Issue 7 (1st April 2017)

• Record Type: Journal Article
• Authors: Rosa, Mònica; Gonzalez-Nunez, Verónica; Barreto-Valer, Katherine; Marcelo, Filipa; Sánchez-Sánchez, Julia; Calle, Luis P.; Arévalo, Juan C.; Rodríguez, Raquel E.; Jiménez-Barbero, Jesús; Arsequell, Gemma; Valencia, Gregorio
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 7(2017)
• Page Start: 2260
• Page End: 2265
• Publication Date: 2017-04-01
• Subjects: BBB Blood brain barrier -- CNS Central nervous system -- [3H]-DPN [3H]-Diprenorphine -- DMEM Dulbecco's modified Eagle's medium -- ENK Enkephalin -- HRMS High resolution mass spectrometry -- HPLC High performance liquid chromatography -- icv intracerebroventricular administration -- ip intraperitoneal administration -- it intrathecal administration -- iv Intravenous administration -- sc Subcutaneous administration -- Nx Naloxone -- NMR Nuclear magnetic resonance -- TSP 2, 2, 3, 3-Tetradeutero-3-trimethylsilylpropionic acid; Neuropeptide -- Opioid receptors -- Neoglycopeptides -- Enkephalin-related -- Glycosylation -- Pharmacology; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.02.052
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 -Met 2, Pro 5 )-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.