Home
  >  
Section 52
  >  
Chapter 51,810

Biological and conformational evaluation of bifunctional compounds for opioid receptor agonists and neurokinin 1 receptor antagonists possessing two penicillamines

Yamamoto, T.; Nair, P.; Jacobsen, N.E.; Kulkarni, V.; Davis, P.; Ma, S.-W.; Navratilova, E.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Lai, J.; Hruby, V.J.

Journal of Medicinal Chemistry 53(15): 5491-5501

2010

ISSN/ISBN: 1520-4804
PMID: 20617791
DOI: 10.1021/jm100157m
Accession: 051809235
Download citation:  
Text
  |  
BibTeX
  |  
RIS
Neuropathic pain states and tolerance to opioids can result from system changes in the CNS, such as up-regulation of the NK1 receptor and substance P, lead to antiopioid effects in ascending or descending pain-signaling pathways. Bifunctional compounds, possessing both the NK1 antagonist pharmacophore and the opioid agonist pharmacophore with delta-selectivity, could counteract these system changes to have significant analgesic efficacy without undesirable side effects. As a result of the introduction of cyclic and topological constraints with penicillamines, 2 (Tyr-cyclo[d-Pen-Gly-Phe-Pen]-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)-Bzl]) was found as the best bifunctional compound with effective NK1 antagonist and potent opioid agonist activities, and 1400-fold delta-selectivity over the mu-receptor. The NMR structural analysis of 2 revealed that the relative positioning of the two connected pharmacophores as well as its cyclic and topological constraints might be responsible for its excellent bifunctional activities as well as its significant delta-opioid selectivity. Together with the observed high metabolic stability, 2 could be considered as a valuable research tool and possibly a promising candidate for a novel analgesic drug.

PDF emailed within 0-6 h: $19.90




Related References

Yamamoto, T.; Nair, P.; Ma, S.-w.; Davis, P.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Lai, J.; Hruby, V.J. 2009: The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moiety Bioorganic and Medicinal Chemistry 17(20): 7337-7343
Yamamoto, T.; Nair, P.; Davis, P.; Ma, S-wu.; Navratilova, E.; Moye, S.; Tumati, S.; Lai, J.; Vanderah, T.W.; Yamamura, H.I.; Porreca, F.; Hruby, V.J. 2007: Design, synthesis, and biological evaluation of novel bifunctional C-terminal-modified peptides for delta/mu opioid receptor agonists and neurokinin-1 receptor antagonists Journal of Medicinal Chemistry 50(12): 2779-2786
Yamamoto, T.; Nair, P.; Jacobsen, N.E.; Vagner, J.; Kulkarni, V.; Davis, P.; Ma, S.-W.; Navratilova, E.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Lai, J.; Hruby, V.J. 2009: Improving metabolic stability by glycosylation: bifunctional peptide derivatives that are opioid receptor agonists and neurokinin 1 receptor antagonists Journal of Medicinal Chemistry 52(16): 5164-5175
Yamamoto, T.; Nair, P.; Jacobsen, N.E.; Davis, P.; Ma, S.-w.; Navratilova, E.; Moye, S.; Lai, J.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Hruby, V.J. 2008: The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists Journal of Medicinal Chemistry 51(20): 6334-6347
Yamamoto, T.; Nair, P.; Vagner, J.; Largent-Milnes, T.; Davis, P.; Ma, S.-W.; Navratilova, E.; Moye, S.; Tumati, S.; Lai, J.; Yamamura, H.I.; Vanderah, T.W.; Porreca, F.; Hruby, V.J. 2008: A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists Journal of Medicinal Chemistry 51(5): 1369-1376
Lee, Y.Sun.; Agnes, R.S.; Badghisi, H.; Davis, P.; Ma, S-wu.; Lai, J.; Porreca, F.; Hruby, V.J. 2006: Design and synthesis of novel hydrazide-linked bifunctional peptides as delta/mu opioid receptor agonists and CCK-1/CCK-2 receptor antagonists Journal of Medicinal Chemistry 49(5): 1773-1780
Harland, A.A.; Yeomans, L.; Griggs, N.W.; Anand, J.P.; Pogozheva, I.D.; Jutkiewicz, E.M.; Traynor, J.R.; Mosberg, H.I. 2015: Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities Journal of Medicinal Chemistry 58(22): 8952-8969
Ballet, S.; Feytens, D.; Buysse, K.; Chung, N.N.; Lemieux, C.; Tumati, S.; Keresztes, A.; Van Duppen, J.; Lai, J.; Varga, E.; Porreca, F.; Schiller, P.W.; Vanden Broeck, J.; Tourwé, D. 2011: Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist Journal of Medicinal Chemistry 54(7): 2467-2476
Salamon, Z.; Hruby, V.J.; Tollin, G.; Cowell, S. 2002: Binding of agonists, antagonists and inverse agonists to the human -opioid receptor produces distinctly different conformational states distinguishable by plasmon-waveguide resonance spectroscopy Chemical Biology and Drug Design 60(6): 322-328
Salamon, Z.; Hruby, V.J.; Tollin, G.; Cowell, S. 2002: Binding of agonists, antagonists and inverse agonists to the human delta-opioid receptor produces distinctly different conformational states distinguishable by plasmon-waveguide resonance spectroscopy Journal of Peptide Research: Official Journal of the American Peptide Society 60(6): 322-328
Nair, P.; Yamamoto, T.; Cowell, S.; Kulkarni, V.; Moye, S.; Navratilova, E.; Davis, P.; Ma, S-Wu.; Vanderah, T.W.; Lai, J.; Porreca, F.; Hruby, V.J. 2015: Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities Bioorganic and Medicinal Chemistry Letters 25(17): 3716-3720
Nair, P.; Yamamoto, T.; Largent-Milnes, T.M.; Cowell, S.; Kulkarni, V.; Moye, S.; Navratilova, E.; Davis, P.; Ma, S.-W.; Vanderah, T.W.; Lai, J.; Porreca, F.; Hruby, V.J. 2013: Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities Bioorganic and Medicinal Chemistry Letters 23(17): 4975-4978
Schiller, P.W.; Nguyen, T.M.; Weltrowska, G.; Chung, N.N.; Lemieux, C.; Marsden, B.J.; Wilkes, B.C. 1993: The use of conformational restriction and molecular modeling techniques in the development of receptor-specific opioid peptide agonists and antagonists Nida Research Monograph 134: 238-252
Li, T.; Jinsmaa, Y.; Nedachi, M.; Miyazaki, A.; Tsuda, Y.; Ambo, A.; Sasaki, Y.; Bryant, S.D.; Marczak, E.; Li, Q.; Swartzwelder, H.S.; Lazarus, L.H.; Okada, Y. 2007: Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists Bioorganic and Medicinal Chemistry 15(3): 1237-1251
van Niel, J.C.G.; Schneider, J.; Tzschentke, T.M. 2016: Efficacy of Full µ-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists - Preclinical and Clinical Evidence Drug Research 66(11): 562-570
Androutsou, M.-E.; Saifeddine, M.; Hollenberg, M.D.; Matsoukas, J.; Agelis, G. 2010: Design, synthesis and biological evaluation of non-peptide PAR1 thrombin receptor antagonists based on small bifunctional templates: arginine and phenylalanine side chain groups are keys for receptor activity Amino Acids 38(4): 985-990
Anzini, M.; Canullo, L.; Braile, C.; Cappelli, A.; Gallelli, A.; Vomero, S.; Menziani, M.C.; De Benedetti, P.G.; Rizzo, M.; Collina, S.; Azzolina, O.; Sbacchi, M.; Ghelardini, C.; Galeotti, N. 2003: Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity Journal of Medicinal Chemistry 46(18): 3853-3864
Hirata, T.; Keto, Y.; Nakata, M.; Takeuchi, A.; Funatsu, T.; Akuzawa, S.; Sasamata, M.; Miyata, K. 2008: Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society 20(5): 557-565
Rooney, K.F.; Sewell, R.D. 1989: Evaluation of selective actions of dopamine D-1 and D-2 receptor agonists and antagonists on opioid antinociception European Journal of Pharmacology 168(3): 329-336
Kubota, H.; Fujii, M.; Ikeda, K.; Takeuchi, M.; Shibanuma, T.; Isomura, Y. 1998: Spiro-substituted piperidines as neurokinin receptor antagonists. I. Design and synthesis of (+/-)-N-[2-(3,4-dichlorophenyl)-4-(spiro [isobenzofuran-1(3H),4'piperidin]-1'-yl)butyl]-N-methylbenzamide, YM-35375, as a new lead compound for novel neurokinin receptor antagonists Chemical and Pharmaceutical Bulletin 46(2): 351-354