Discovery of high affinity and ultraselective 5 opioid dipeptide antagonists composed of 2',6'-dimethyl- L-tyrosyl (Dmt) and 1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (Tic) served as the basis for the conformationally restricted diketopiperazine cyc/o(Dmt-Tic) and related open chain analogues. These peptides primarily bind to 5 opioid receptors: c(Dmt-Tic) displayed 30- to 50-fold higher δ affinity (Kfi) than its diastereoisomeric analogues and more than 4000-fold greater than its Tyr cognate; all of the c(Tyr-Tic) analogues were essentially inactive; c[(/V-methyl)Dmt-Tic] lost 5- fold in Κ,δ, while Κ,μ increased 10-fold to yield a nonselective peptide; and the c(Dmt-Phe) series exhibited considerably reduced binding which indicated a synergism between Dmt and Tic in the binding mechanism. Whereas acetyl-Dmt-Tic linear peptides weakly interacted with opioid receptors, Ac-Dmt-Tic-NH2, exhibited better δ antagonist activity than c(Dmt-Tic) and greater δ receptor selectivity (Κ\μ/Κβ = 570). A three point attachment hypothesis for the interaction between c(Dmt-Tic) and the δ receptor was proposed: hydrophobicity imparted by the aromatic rings and the methyl groups of Dmt, hydrogen bonding through the tyramine hydroxyl group, and cation-π interactions were suggested as contributing factors in binding the diketopiperazine in the receptor pocket. Although c(Dmt-Tic) exhibited a weak antagonist activity with mouse vas deferens, this diketopiperazine may provide a scaffolding for the formation of more potent antagonists for potential therapeutic applications.
Opioid diketopiperazines: Synthesis and activity of a prototypic class of opioid antagonists
BALBONI, Gianfranco;GUERRINI, Remo;SALVADORI, Severo;
1997
Abstract
Discovery of high affinity and ultraselective 5 opioid dipeptide antagonists composed of 2',6'-dimethyl- L-tyrosyl (Dmt) and 1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (Tic) served as the basis for the conformationally restricted diketopiperazine cyc/o(Dmt-Tic) and related open chain analogues. These peptides primarily bind to 5 opioid receptors: c(Dmt-Tic) displayed 30- to 50-fold higher δ affinity (Kfi) than its diastereoisomeric analogues and more than 4000-fold greater than its Tyr cognate; all of the c(Tyr-Tic) analogues were essentially inactive; c[(/V-methyl)Dmt-Tic] lost 5- fold in Κ,δ, while Κ,μ increased 10-fold to yield a nonselective peptide; and the c(Dmt-Phe) series exhibited considerably reduced binding which indicated a synergism between Dmt and Tic in the binding mechanism. Whereas acetyl-Dmt-Tic linear peptides weakly interacted with opioid receptors, Ac-Dmt-Tic-NH2, exhibited better δ antagonist activity than c(Dmt-Tic) and greater δ receptor selectivity (Κ\μ/Κβ = 570). A three point attachment hypothesis for the interaction between c(Dmt-Tic) and the δ receptor was proposed: hydrophobicity imparted by the aromatic rings and the methyl groups of Dmt, hydrogen bonding through the tyramine hydroxyl group, and cation-π interactions were suggested as contributing factors in binding the diketopiperazine in the receptor pocket. Although c(Dmt-Tic) exhibited a weak antagonist activity with mouse vas deferens, this diketopiperazine may provide a scaffolding for the formation of more potent antagonists for potential therapeutic applications.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
