Highly potent side chain-main chain cyclized dermorphin-deltorphin analogues: an integrated approach including synthesis, bioassays, NMR spectroscopy and molecular modelling.
Our continuing efforts to study structure-activity relationships of peptide opioids have resulted in the synthesis of a series of cyclic opioids related to dermorphins and deltorphins. The biological activities of the compounds have been determined and the conformational analyses carried out using 1H-NMR spectroscopy and molecular modelling. The three compounds in the series Tyr-c[D-Orn-Phe-Ala], Tyr-c[D-Lys-Phe-Ala], and Tyr-c[A2bu-Phe-Ala-Leu] are cyclized via a lactam bridge from the side-chain of the residue at the second position with the carboxyl terminus of each compound. The molecules incorporate 12-, 13- and 14-membered rings, respectively. They include a phenylalanine at the third position which is a distinguishing characteristic of dermorphins and deltorphins. The guinea pig ileum and mouse vas deferens assays show that the compounds are highly active at both mu- and delta-opioid receptors. The compounds are all highly effective antinociceptive agents as measured by the intrathecal rat hot plate test. Conformational analyses of the molecules indicate that they can adopt topochemical arrays required for bioactivity at both mu- and delta-receptors which explains their high activity in both guinea pig ileum and mouse vas deferens in vitro assays. The results support our models for mu- and delta-receptor activity for constrained peptide opioids.
Ro
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Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0343, USA.
Zhu
Q
Q
Lee
C W
CW
Goodman
M
M
Darlak
K
K
Spatola
A F
AF
Chung
N N
NN
Schiller
P W
PW
Malmberg
A B
AB
Yaksh
T L
TL
D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001681:Biological Assay; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013329:Structure-Activity Relationship
D000700:Analgesics; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C059567:deltorphin; C030058:dermorphin