Crystal structures of dipeptides containing the Dmt-Tic pharmacophore.
The crystal structures of three analogues of the potent delta-opioid receptor antagonist H-Dmt-Tic-OH (2',6'-dimethyl-L-tyrosine-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylate), N,N (CH(3))(2)-Dmt-Tic-OH (1), H-Dmt-Tic-NH-1-adamantane (2), and N,N(CH(3))(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 P2(1), and 2 crystallized in the tetragonal space group P4(3). Common backbone atom superimpositions of structures derived from X-ray diffraction studies resulted in root-mean-square (rms) deviations of 0.2-0.5 A, while all-atom superimpositions gave higher rms deviations from 0.8 to 1.2 A. Intramolecular distances between the aromatic ring centers of Dmt and Tic were 5.1 A in 1, 6.3 A in 2, and 6.5 A in 3. The orientation of the C-terminal substituent 1-adamantane in 2 and 3 was affected by differences in the psi torsion angles and strong hydrogen bonds with adjacent molecules. Despite the high delta-opioid receptor affinity exhibited by each analogue (K(i) < 0.3 nM), high mu receptor affinity (K(i) < 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 mu-agonism, while 3 also had potent delta-antagonist activity. Those data demonstrated that a C-terminal hydrophobic group was an important determinant for eliciting mu-agonism, whereas N-methylation maintained delta-antagonism. Furthermore, the structural results support the hypothesis that expanded dimensions between aromatic nuclei is important for acquiring mu-agonism.
Bryant
Sharon D
SD
Peptide Neurochemistry, LCBRA, National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop C3-04, Research Triangle Park, North Carolina 27709, USA. bryant2@niehs.nih.gov
George
Clifford
C
Flippen-Anderson
Judith L
JL
Deschamps
Jeffrey R
JR
Salvadori
Severo
S
Balboni
Gianfranco
G
Guerrini
Remo
R
Lazarus
Lawrence H
LH
D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D018847:Opioid Peptides / Q000737:chemistry*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*
C434929:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carbonylamino-1-adamantane; C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D004151:Dipeptides; D007546:Isoquinolines; C417742:N,N(Me)2-dimethyl-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-OH; C402273:N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl 1-adamantane amide; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D014443:Tyrosine; D000218:Adamantane