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Crystal Structures of Dipeptides Containing the Dmt-Tic Pharmacophore

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Peptide Neurochemistry, LCBRA, National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop C3-04, Research Triangle Park, North Carolina 27709, Naval Research Laboratory, Washington, D.C., Faculty of Pharmaceutical Science and Biotechnology Center, University of Ferrara, I-44100 Ferrara, Italy, and Department of Toxicology, University of Cagliary, I09126 Cagliary, Italy
Cite this: J. Med. Chem. 2002, 45, 25, 5506–5513
Publication Date (Web):October 31, 2002
https://doi.org/10.1021/jm020330p
Copyright © 2002 American Chemical Society

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    Abstract

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    The crystal structures of three analogues of the potent δ-opioid receptor antagonist H-Dmt-Tic-OH (2‘,6‘-dimethyl-l-tyrosine-l-1,2,3,4-tetrahydroisoquinoline-3-carboxylate), N,N (CH3)2-Dmt-Tic-OH (1), H-Dmt-Tic-NH-1-adamantane (2), and N,N(CH3)2-Dmt-Tic-NH-1-adamantane (3) were determined by X-ray single-crystal analysis. Crystals of 1 were grown by slow evaporation, while those of 2 and 3 were grown by vapor diffusion. Compounds 1 and 3 crystallized in the monoclinic space group P21, and 2 crystallized in the tetragonal space group P43. Common backbone atom superimpositions of structures derived from X-ray diffraction studies resulted in root-mean-square (rms) deviations of 0.2−0.5 Å, while all-atom superimpositions gave higher rms deviations from 0.8 to 1.2 Å. Intramolecular distances between the aromatic ring centers of Dmt and Tic were 5.1 Å in 1, 6.3 Å in 2, and 6.5 Å in 3. The orientation of the C-terminal substituent 1-adamantane in 2 and 3 was affected by differences in the ψ torsion angles and strong hydrogen bonds with adjacent molecules. Despite the high δ-opioid receptor affinity exhibited by each analogue (Ki < 0.3 nM), high μ-receptor affinity (Ki < 1 nM) was manifested only with the bulky C-terminal 1-adamantane analogues 2 and 3. Furthermore, the bioactivity of both 2 and 3 exhibited μ-agonism, while 3 also had potent δ-antagonist activity. Those data demonstrated that a C-terminal hydrophobic group was an important determinant for eliciting μ-agonism, whereas N-methylation maintained δ-antagonism. Furthermore, the structural results support the hypothesis that expanded dimensions between aromatic nuclei is important for acquiring μ-agonism.

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     To whom correspondence should be addressed. Phone:  1-919-541-4962. Fax:  1-919-541-0696. E-mail:  [email protected].

     National Institute of Environmental Health Sciences.

     Naval Research Laboratory.

    §

     University of Ferrara.

     University of Cagliary.

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    Crystal data, atomic coordinates, and equivalent isotropic displacement parameters, anisotropic displacement parameters, bond lengths and angles, torsion angles, hydrogen coordinates, isotropic displacement parameters, and observed hydrogen bonds for each of the three compounds. This material is available free of charge via the Internet at http://pubs.acs.org. In addition, tables of coordinates, bond distances, bond angles, and anisotropic thermal parameters have been deposited with the Crystallographic Data Centre, Cambridge, CB2, 1EW, England.

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    Cited By

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    1. Lukas Wanka, Khalid Iqbal, and Peter R. Schreiner . The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives. Chemical Reviews 2013, 113 (5) , 3516-3604. https://doi.org/10.1021/cr100264t
    2. Joe Liu, Daniel Obando, Vivian Liao, Tulip Lifa, Rachel Codd. The many faces of the adamantyl group in drug design. European Journal of Medicinal Chemistry 2011, 46 (6) , 1949-1963. https://doi.org/10.1016/j.ejmech.2011.01.047
    3. . 3D Quantitative and Qualitative Structure-Activity Relationships of the δ -Opioid Receptor Antagonists. Bulletin of the Korean Chemical Society 2008, 656-662. https://doi.org/10.5012/bkcs.2008.29.3.656
    4. Jeffrey R. Deschamps. The Role of Crystallography in Drug Design. 2008, 343-355. https://doi.org/10.1007/978-0-387-76678-2_21
    5. Jeffrey R. Deschamps. The role of crystallography in drug design. The AAPS Journal 2005, 7 (4) , E813-E819. https://doi.org/10.1208/aapsj070478
    6. Henry J. Breslin, Tamara A. Miskowski, Bryan M. Rafferty, Santosh V. Coutinho, Jeffrey M. Palmer, Nathaniel H. Wallace, Craig R. Schneider, Edward S. Kimball, Sui-Po Zhang, Jian Li, Raymond W. Colburn, Dennis J. Stone, Rebecca P. Martinez, Wei He. Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders. Journal of Medicinal Chemistry 2004, 47 (21) , 5009-5020. https://doi.org/10.1021/jm030548r
    7. Gianfranco Balboni, Severo Salvadori, Remo Guerrini, Lucia Negri, Elisa Giannini, Sharon D. Bryant, Yunden Jinsmaa, Lawrence H. Lazarus. Direct Influence of C-Terminally Substituted Amino Acids in the Dmt−Tic Pharmacophore on δ-Opioid Receptor Selectivity and Antagonism. Journal of Medicinal Chemistry 2004, 47 (16) , 4066-4071. https://doi.org/10.1021/jm040033f
    8. Yunden Jinsmaa, Anna Miyazaki, Yoshio Fujita, Tingyou Li, Yutaka Fujisawa, Kimitaka Shiotani, Yuko Tsuda, Toshio Yokoi, Akihiro Ambo, Yusuke Sasaki, Sharon D. Bryant, Lawrence H. Lazarus, Yoshio Okada. Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH 2 ) n ]-2(1 H )-pyrazinone with Central-Mediated Analgesia. Journal of Medicinal Chemistry 2004, 47 (10) , 2599-2610. https://doi.org/10.1021/jm0304616
    9. Gianfranco Balboni, Severo Salvadori, Remo Guerrini, Lucia Negri, Elisa Giannini, Sharon D Bryant, Yunden Jinsmaa, Lawrence H Lazarus. Synthesis and opioid activity of N,N-Dimethyl-Dmt-Tic-NH-CH(R)-R′ analogues: acquisition of potent δ antagonism. Bioorganic & Medicinal Chemistry 2003, 11 (24) , 5435-5441. https://doi.org/10.1016/j.bmc.2003.09.039
    10. Hisanori Ueki, Trevor K Ellis, Masood A Khan, Vadim A Soloshonok. Highly diastereoselective synthesis of new, carbostyril-based type of conformationally-constrained β-phenylserines. Tetrahedron 2003, 59 (37) , 7301-7306. https://doi.org/10.1016/S0040-4020(03)01172-4
    11. Yoshio Okada, Yuko Tsuda, Yoshio Fujita, Toshio Yokoi, Yusuke Sasaki, Akihiro Ambo, Ryoji Konishi, Mitsuhiro Nagata, Severo Salvadori, Yunden Jinsmaa, Sharon D. Bryant, Lawrence H. Lazarus. Unique High-Affinity Synthetic μ-Opioid Receptor Agonists with Central- and Systemic-Mediated Analgesia. Journal of Medicinal Chemistry 2003, 46 (15) , 3201-3209. https://doi.org/10.1021/jm020459z
    12. Sharon D. Bryant, Yunden Jinsmaa, Severo Salvadori, Yoshio Okada, Lawrence H. Lazarus. Dmt and opioid peptides: A potent alliance. Peptide Science 2003, 71 (2) , 86-102. https://doi.org/10.1002/bip.10399
    13. Yeon Sun Lee, Joel Nyberg, Sharif Moye, Richard Agnes, Adriano Mollica, Peg Davis, Shou-Wu Ma, Josephin Lai, Frank Porreca, Ruben Vardanyan, Victor J. Hruby. Development of μ Opioid Receptor Selective 4-Anilinidopiperidine Analogs. , 591-592. https://doi.org/10.1007/978-0-387-26575-9_258

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