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 (CH3)(2)-Dmt-Tic-OH (1), H-Dmt-Tic-NH-1-adamantane (2), and NN(CH3)2-Dmt-Tic-NH-1-adamantane (3) were determined by X-ray single-crystal analysis. Crystals of I 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 Angstrom, while all-atom superimpositions gave higher rms deviations from 0.8 to 1.2 Angstrom. Intramolecular distances between the aromatic ring centers of Dmt and Tic were 5.1 Angstrom in 1, 6.3 Angstrom in 2, and 6.5 Angstrom 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), highy-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.