A new class of δ opioid antagonists was recently discovered in which the sequence Tyr-Tic was used as a message domain. The substitution of Tyr1 by Dmt enhanced the δ selectivity and antagonist activity. The excellent properties of these ligands stimulated us to prepare the corresponding tritiated derivatives. Peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, with a reduction in opioid activity. To avoid this side-reaction we synthesised the N,N-dimethylated analogue (N,N(Me)2-Dmt-Tic-OH), which was found to be stable. On the basis of this result, we prepared diiodinated analogues of H-Dmt-Tic-OH and N,N(Me)2-Dmt-Tic-OH to undergo catalytic dehalotritiation. Products of high specific radioactivity were obtained: 44.67 Ci/mmol for [3H]Dmt-Tic-OH and 59.88 Ci/mmol for [3H]N,N(Me)2-Dmt-Tic-OH.

Synthesis of 2',6'-dimethyltyrosine containing tritiated delta oioid-receptor selective antagonist dipeptide ligands with extraordinary affinity

BALBONI, GIANFRANCO;
1998

Abstract

A new class of δ opioid antagonists was recently discovered in which the sequence Tyr-Tic was used as a message domain. The substitution of Tyr1 by Dmt enhanced the δ selectivity and antagonist activity. The excellent properties of these ligands stimulated us to prepare the corresponding tritiated derivatives. Peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, with a reduction in opioid activity. To avoid this side-reaction we synthesised the N,N-dimethylated analogue (N,N(Me)2-Dmt-Tic-OH), which was found to be stable. On the basis of this result, we prepared diiodinated analogues of H-Dmt-Tic-OH and N,N(Me)2-Dmt-Tic-OH to undergo catalytic dehalotritiation. Products of high specific radioactivity were obtained: 44.67 Ci/mmol for [3H]Dmt-Tic-OH and 59.88 Ci/mmol for [3H]N,N(Me)2-Dmt-Tic-OH.
delta opioid antagonist; dipeptide; tritium
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/6793
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