Crystal structures of dipeptides containing the Dmt-Tic pharmacophore

The crystal structures of three analogues of the potent ä-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 ã torsion angles and strong hydrogen bonds with adjacent molecules. Despite the high ä-opioid receptor affinity exhibited by each analogue (Ki < 0.3 nM), high í-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 í-agonism, while 3 also had potent ä-antagonist activity. Those data demonstrated that a C-terminal hydrophobic group was an important determinant for eliciting í-agonism, whereas N-methylation maintained ä-antagonism. Furthermore, the structural results support the hypothesis that expanded dimensions between aromatic nuclei is important for acquiring í-agonism