To discriminate between two general models of antagonism (participation and allosteric), an opioid antagonist lacking the basic nitrogen of tyramine was designed and characterized. Cyclo-[Tyr(Me),-Tic-], the diketopiperazine of 2,6-dimethyltyrosyl- 1,2,3,4-tetrahydroisoquinoline3-- carboxylic acid, is a partially rigid opioid antagonist; its pA2 (5.8) is one smaller than that of N,N-bisallyl-enkephalin but it has a very high binding affinity (10 nM) and has a 8 selectivity (66 with respect to the binding top receptors) higher than that of naltrindole. The conformational state of this diketopiperazi ne, studied under a variety of solvent and temperature conditions by NMR and molecular dynamics, can be described in terms of only three conformers whose relative populations vary widely with solvent. Only one of the three conformers, characterized by a 90" arrangement of the aromatic rings of Tyr(Me), and Tic similar to those of rigid agonists and of the bioactive conformation of the corresponding linear antagonist, is consistent with the antagonist activity. This finding favors the participation model among the general niechanisms proposed to explain antagonism. Due to the simple composition of the conformational mixture and to the rigidity of the molecule, it is possible to propose a quantitative explanation for the. discrepancy between the very high binding affinity (10 nM) and the fairly small in mouse vas deferens value (1.5 yM).
Design and solution structure of a partially rigid opioid antagonist lacking the basic center - Models of antagonism
BALBONI, Gianfranco;GUERRINI, Remo;SALVADORI, Severo;
1997
Abstract
To discriminate between two general models of antagonism (participation and allosteric), an opioid antagonist lacking the basic nitrogen of tyramine was designed and characterized. Cyclo-[Tyr(Me),-Tic-], the diketopiperazine of 2,6-dimethyltyrosyl- 1,2,3,4-tetrahydroisoquinoline3-- carboxylic acid, is a partially rigid opioid antagonist; its pA2 (5.8) is one smaller than that of N,N-bisallyl-enkephalin but it has a very high binding affinity (10 nM) and has a 8 selectivity (66 with respect to the binding top receptors) higher than that of naltrindole. The conformational state of this diketopiperazi ne, studied under a variety of solvent and temperature conditions by NMR and molecular dynamics, can be described in terms of only three conformers whose relative populations vary widely with solvent. Only one of the three conformers, characterized by a 90" arrangement of the aromatic rings of Tyr(Me), and Tic similar to those of rigid agonists and of the bioactive conformation of the corresponding linear antagonist, is consistent with the antagonist activity. This finding favors the participation model among the general niechanisms proposed to explain antagonism. Due to the simple composition of the conformational mixture and to the rigidity of the molecule, it is possible to propose a quantitative explanation for the. discrepancy between the very high binding affinity (10 nM) and the fairly small in mouse vas deferens value (1.5 yM).I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
