Structure-activity relationships of dermorphin analogues containing N-substituted amino acids in the 2-position of the peptide sequence.

Abstract

A series of dermorphin analogues containing an N-alkylated amino-acid residue Xaa in the 2-position of the peptide sequence was synthesized (Xaa = N-methylalanine, proline, pipecolic acid, N-methylphenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Tic]). These peptides have the potential of assuming a cis Tyr1-Xaa2 peptide bond. Their in vitro opioid activity profiles were determined in mu- and delta-receptor-representative binding assays and bioassays. Aside from [D-Pro2]dermorphin, all analogues showed high affinity for mu- and/or delta-opioid receptors. Whereas most compounds were found to be full mu-agonists in the guinea pig ileum (GPI) assay, [Tic2]dermorphin (compound 7) was a partial mu-agonist. Replacement of Gly4 in 7 with Phe resulted in an analogue (8) with weak mu-antagonist activity. Furthermore, analogues 7 and 8 both were potent delta-antagonists (Ke = 3-40 nM) against the delta-agonists Leu-enkephalin, DPDPE and deltorphin I in the mouse vas deferens (MVD) assay. Compound 3, containing L-Pro in the 2-position, turned out to be one of the most mu-receptor-selective linear dermorphin analogues reported to date. Low-temperature HPLC experiments using micropellicular octadecyl silica as stationary phase revealed conformational heterogeneity of the dermorphin analogues which was ascribed to cis-trans isomerization around the Tyr1-Xaa2- and Tyr5-Pro6 peptide bonds. In the case of analogue 7 four separate peaks corresponding to the four possible isomers were apparent at -5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: R Schmidt, A Kálmán, N N Chung, C Lemieux, C Horváth, P W Schiller
• Journal: International journal of peptide and protein research (Int J Pept Protein Res) Vol. 46 Issue 1 Pg. 47-55 (Jul 1995) ISSN: 0367-8377 [Print] Denmark
• PMID: 7558596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Narcotic Antagonists
• Oligopeptides
• Opioid Peptides
• Receptors, Opioid, delta
• Receptors, Opioid, mu
• dermorphin

Topics

• Amino Acid Sequence
• Animals
• Brain (metabolism)
• Cell Membrane (metabolism)
• Chromatography, High Pressure Liquid
• Guinea Pigs
• Ileum (metabolism)
• Male
• Methylation
• Mice
• Molecular Sequence Data
• Narcotic Antagonists (chemical synthesis, chemistry, metabolism, pharmacology)
• Oligopeptides (chemistry, metabolism, pharmacology)
• Opioid Peptides (chemical synthesis, chemistry, metabolism, pharmacology)
• Rats
• Receptors, Opioid, delta (agonists, antagonists & inhibitors, metabolism)
• Receptors, Opioid, mu (agonists, antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Temperature
• Vas Deferens (metabolism)