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Structural modification and biological evaluation of Dmt1-DALDA analogues

(2011) PHARMACOLOGICAL REPORTS. 63(1). p.231-231
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Abstract
The highly charged tetrapeptide Dmt-DALDA (Dmt-D-Arg-Phe-Lys-NH2) has been previously identified as a potent μ-opioid receptor agonist1 and serves as a lead compound for the further development of novel therapeutic (peptidic) opioid analgesics. The present work describes structural modifications of the peptide in order to determine the role of the charges, role of N-methylation, and role of conformation. All prepared compounds have been tested for their in vitro affinity and activity (guinea pig ileum GPI and mouse vas deferens MVD assays), their in vitro permeability (caco-2 test) and in vivo tissue distribution, in- and efflux into and out of mouse brain. These experimental data indicate that : i) side-chain charges are not essential for in vitro activity, ii) the guanidine group of D-Arg2 is important for the blood-brain permeability iii) the conformational constraint of the Phe residue by the benzazepine ring results in highly potent compounds, but is not compatible with the Lys side chain, which can best be removed for high potency. A more detailed discussion of the obtained results will be presented. References: 1. Shimoyama, M.; Szeto, H.H.; Schiller, P.W.; Tagaito, Y.; Tokairin, H.; Eun, C.M., Shimoyama N. Pharmacology 2008, 83, 33-37. 2. Zhao, K.; Luo, G., Zhao, G.-M.; Schiller, P.W.; Szeto, H.H. J. Pharmacol. Exp. Ther. 2003, 304, 425-432.

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Chicago
Novoa, Alexandre, Sylvia Van Dorpe, Evelien Wynendaele, Nga Chung, Carole Lemieux, Peter W Schiller, Dirk Tourwé, Bart De Spiegeleer, and Steven Ballet. 2011. “Structural Modification and Biological Evaluation of Dmt1-DALDA Analogues.” In Pharmacological Reports, 63:231–231.
APA
Novoa, A., Van Dorpe, S., Wynendaele, E., Chung, N., Lemieux, C., Schiller, P. W., Tourwé, D., et al. (2011). Structural modification and biological evaluation of Dmt1-DALDA analogues. PHARMACOLOGICAL REPORTS (Vol. 63, pp. 231–231). Presented at the European Opioid Conference 2011.
Vancouver
1.
Novoa A, Van Dorpe S, Wynendaele E, Chung N, Lemieux C, Schiller PW, et al. Structural modification and biological evaluation of Dmt1-DALDA analogues. PHARMACOLOGICAL REPORTS. 2011. p. 231–231.
MLA
Novoa, Alexandre, Sylvia Van Dorpe, Evelien Wynendaele, et al. “Structural Modification and Biological Evaluation of Dmt1-DALDA Analogues.” Pharmacological Reports. Vol. 63. 2011. 231–231. Print.
@inproceedings{1229933,
  abstract     = {The highly charged tetrapeptide Dmt-DALDA (Dmt-D-Arg-Phe-Lys-NH2) has been previously identified as a potent \ensuremath{\mu}-opioid receptor agonist1 and serves as a lead compound for the further development of novel therapeutic (peptidic) opioid analgesics. The present work describes structural modifications of the peptide in order to determine the role of the charges, role of N-methylation, and role of conformation. All prepared compounds have been tested for their in vitro affinity and activity (guinea pig ileum GPI and mouse vas deferens MVD assays), their in vitro permeability (caco-2 test) and in vivo tissue distribution, in- and efflux into and out of mouse brain. These experimental data indicate that : i) side-chain charges are not essential for in vitro activity, ii) the guanidine group of D-Arg2 is important for the blood-brain permeability iii) the conformational constraint of the Phe residue by the benzazepine ring results in highly potent compounds, but is not compatible with the Lys side chain, which can best be removed for high potency. A more detailed discussion of the obtained results will be presented. References: 1. Shimoyama, M.; Szeto, H.H.; Schiller, P.W.; Tagaito, Y.; Tokairin, H.; Eun, C.M., Shimoyama N. Pharmacology 2008, 83, 33-37. 2. Zhao, K.; Luo, G., Zhao, G.-M.; Schiller, P.W.; Szeto, H.H. J. Pharmacol. Exp. Ther. 2003, 304, 425-432.},
  author       = {Novoa, Alexandre and Van Dorpe, Sylvia and Wynendaele, Evelien and Chung, Nga and Lemieux, Carole and Schiller, Peter W and Tourw{\'e}, Dirk and De Spiegeleer, Bart and Ballet, Steven},
  booktitle    = {PHARMACOLOGICAL REPORTS},
  issn         = {1734-1140},
  language     = {eng},
  location     = {Krakow, Poland},
  number       = {1},
  pages        = {231--231},
  title        = {Structural modification and biological evaluation of Dmt1-DALDA analogues},
  volume       = {63},
  year         = {2011},
}

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