Bioactive models for a δ opioid receptor antagonist are proposed based on the structurally rigid, diketopiperazine containing cyclo 2',6'-dimethyl-L-tyrosyl (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Monte Carlo conformational analysis of c(Dmt- Tic) generated three low energy clusters (I - III) of conformers. The lowest energy conformer representing cluster I superimposed best with the X-ray crystal structures of c(Tyr-Tic), an inactive diketopiperazine with similar framework as c(Dmt-Tic), with H-Tyr-Tic- NH2, a dipeptide of moderate δ opioid affinity and lacking bioactivity, and with H-Tyr-Tic-Phe-Phe-OH (TIPP), a selective and potent δ opioid receptor antagonist. Clusters I and II superimposed best with three different overlays of naltrindole, a potent δ opiate antagonist, and with two other H-Tyr-Tic-NH δ opioid antagonist pharmacophores proposed by Temussi et a/. (1994) and Wilkes and Schiller (1995). The 3-dimensional topography of these two clusters of c(Dmt-Tic) conformations may represent bioactive models for interaction of an antagonist at δ opioid receptors. Cluster I conformers exhibited gauche" (- 64°) and gauche* (53°) orientations of the side chains Dmt and Tic, respectively, while cluster II contained frans (179°) and gauche* (62°) orientations of those side-chains. Aromatic ring distances were 5.4 A for cluster I conformations and 8.2 A for cluster II structures. Orientation about the peptide bond N-C' was c/s (- 5° and 3°) for both clusters, respectively. These structural features may provide optimal alignment of the physicochemical moieties important for δ opioid receptor interaction, such as the hydrophobic methyl groups of Dmt, hydrogen bonding of the dimethyltyrosine hydroxyl group within the receptor pocket and cation-π interactions involving the aromatic rings of Dmt and Tic, as profiled by the three point attachment hypothesis.
Opioid diketopiperazines: Refinement of the delta opioid antagonist pharmacophore
BALBONI, Gianfranco;GUERRINI, Remo;SALVADORI, Severo;
1997
Abstract
Bioactive models for a δ opioid receptor antagonist are proposed based on the structurally rigid, diketopiperazine containing cyclo 2',6'-dimethyl-L-tyrosyl (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Monte Carlo conformational analysis of c(Dmt- Tic) generated three low energy clusters (I - III) of conformers. The lowest energy conformer representing cluster I superimposed best with the X-ray crystal structures of c(Tyr-Tic), an inactive diketopiperazine with similar framework as c(Dmt-Tic), with H-Tyr-Tic- NH2, a dipeptide of moderate δ opioid affinity and lacking bioactivity, and with H-Tyr-Tic-Phe-Phe-OH (TIPP), a selective and potent δ opioid receptor antagonist. Clusters I and II superimposed best with three different overlays of naltrindole, a potent δ opiate antagonist, and with two other H-Tyr-Tic-NH δ opioid antagonist pharmacophores proposed by Temussi et a/. (1994) and Wilkes and Schiller (1995). The 3-dimensional topography of these two clusters of c(Dmt-Tic) conformations may represent bioactive models for interaction of an antagonist at δ opioid receptors. Cluster I conformers exhibited gauche" (- 64°) and gauche* (53°) orientations of the side chains Dmt and Tic, respectively, while cluster II contained frans (179°) and gauche* (62°) orientations of those side-chains. Aromatic ring distances were 5.4 A for cluster I conformations and 8.2 A for cluster II structures. Orientation about the peptide bond N-C' was c/s (- 5° and 3°) for both clusters, respectively. These structural features may provide optimal alignment of the physicochemical moieties important for δ opioid receptor interaction, such as the hydrophobic methyl groups of Dmt, hydrogen bonding of the dimethyltyrosine hydroxyl group within the receptor pocket and cation-π interactions involving the aromatic rings of Dmt and Tic, as profiled by the three point attachment hypothesis.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
