Abstract
Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM Ki's). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2237-2246 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 57 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 27 2014 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin? / Li, Yingxue; St. Louis, Lindsay; Knapp, Brian I.; Muthu, Dhanasekaran; Anglin, Bobbi; Giuvelis, Denise; Bidlack, Jean M.; Bilsky, Edward J.; Polt, Robin L.
In: Journal of Medicinal Chemistry, Vol. 57, No. 6, 27.03.2014, p. 2237-2246.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin?
AU - Li, Yingxue
AU - St. Louis, Lindsay
AU - Knapp, Brian I.
AU - Muthu, Dhanasekaran
AU - Anglin, Bobbi
AU - Giuvelis, Denise
AU - Bidlack, Jean M.
AU - Bilsky, Edward J.
AU - Polt, Robin L
PY - 2014/3/27
Y1 - 2014/3/27
N2 - Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM Ki's). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.
AB - Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM Ki's). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.
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UR - http://www.scopus.com/inward/citedby.url?scp=84897387550&partnerID=8YFLogxK
U2 - 10.1021/jm400879w
DO - 10.1021/jm400879w
M3 - Article
VL - 57
SP - 2237
EP - 2246
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 6
ER -