title: Endomorphin-1 analogues containing beta-proline are mu-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance.
abstract: In this paper we describe the synthesis and affinity toward the mu-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH(2) (1), by substituting each amino acid in turn with its homologue. The ability to bind mu-opioid receptors depends on the beta-amino acid, and in particular 4, which contains beta-L-Pro, has a K(I) in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the mu-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as mu-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential mu-opioid receptor agonists.
authors.affiliation: Dipartimento di Chimica G. Ciamician, via Selmi 2, Università degli Studi di Bologna, 40126-Bologna, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cardillo
authors.forename: Luca
authors.initials: L
authors.lastname: Gentilucci
authors.forename: Ahmed R
authors.initials: AR
authors.lastname: Qasem
authors.forename: Fabio
authors.initials: F
authors.lastname: Sgarzi
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D018826:CD13 Antigens / Q000737:chemistry; D002268:Carboxypeptidases / Q000737:chemistry; D043402:Cathepsin A; D002918:Chymotrypsin / Q000737:chemistry; D000242:Cyclic AMP / Q000096:biosynthesis; D006868:Hydrolysis; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D011392:Proline; D000242:Cyclic AMP; D002268:Carboxypeptidases; D018826:CD13 Antigens; D043402:Cathepsin A; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; C072401:beta-proline