Distinct conformational preferences of three cyclic beta-casomorphin-5 analogs determined using NMR spectroscopy and theoretical analysis.
The conformational properties of three cyclic beta-casomorphin analogs based on the general formula H-Tyr-c[-D-Orn-2-Nal-D-Pro-Xaa-] (2-Nal = 2-naphthylalanine; Xaa = D-Ala, Sar or NMe-Ala) in DMSO solution were investigated using NMR spectroscopy in conjunction with molecular modeling techniques. The D-Ala5- and Sar5-analogs (compounds 1 and 2 respectively) are potent mixed mu-agonist/delta-antagonists with high mu- and delta-opioid receptor affinities, whereas the NMe-Ala5-analog (compound 3) is a potent mu-agonist and a weak partial delta-agonist. Distinct conformational differences emerged for the three compounds studied. Flexibility in the bare ring structures was found to increase in the order 3 < 2 < 1. The increased structural rigidity of 3 may be responsible for its low delta-receptor affinity as compared to the two other analogs. A low fractional population of conformers containing two cis peptide bonds was found for compound 2 but not for analog 1 or 3. Initial evidence for this observation was obtained from NMR differential line-broadening experiments and later confirmed by molecular mechanics simulations. Comparison of the temperature dependence of amide proton chemical shifts acquired for the three cyclic analogs indicate a large degree of intramolecular hydrogen bonding for 1 but not for the other two peptides.
Carpenter
K A
KA
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Schiller
P W
PW
Schmidt
R
R
Wilkes
B C
BC
D004723:Endorphins / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009292:Narcotic Antagonists; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000819:agonists; D013329:Structure-Activity Relationship
D004723:Endorphins; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; C034812:beta-casomorphin 5