Design and Solution Structure of a Partially Rigid Opioid Antagonist Lacking the Basic Center — Models of Antagonism

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-tetrahydroisoquinoline-3-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 t o p 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).Keywords: antagonism ; NMR ; opioid ; molecular dynamics ; selectivity.Prevailing ideas on the cause of antagonism of natural hormones can be grouped [I] into two very general models: one, called the participation model, attributes antagonism to the lack of a key group essential to elicit agonism [2, 31; and the other is more general and attributes antagonism to a more or less pronounced misfit of the whole molecule in the receptor (this second model can be simply described as an allosteric model [41). The great number of natural and synthetic opioids (agonists and antagonists) and the variety of their chemical constitution offer an opportunity to discriminate between these two models.The message domains 151 of opioid agonists, either alkaloids [6) or peptides [7], share common structural features, the most prominent of which is the tyramine moiety including the positive charge of its basic nitrogen and, often, a second aromatic ring. Opioid antagonists are molecules with a chemical constitution very similar to those of the corresponding agonists ; accordingly, it is not easy to discriminate between the two quoted models of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. antagonism. They have generally been obtained by substitution of one or more protons of the basic nitrogen, common to all opioids, with an appropriate substituent, generally an ally1 or a cyclopropylmethyl group. Such a substitution, in agreement with the participation model [ 1 -31, may either shield the positive charge or displace it from a critical interacting position. In the latter case however, it is conceivabl...

Natural peptide analgesics: the role of solution conformation

“…On the other hand, peptides cannot be studied in truly apolar solvents because they are not sufficiently soluble. Solubility is precluded by the presence, on peptides, of charged groups, in particular the N-terminal ammonium group that is essential for an interaction with the receptor, at least for agonists [98]. A possible way to circumvent this difficulty was proposed by Temussi et al [99].…”

Design of μ selective opioid dipeptide antagonists

“…In fact, Tyr‐Tic‐NH 2 itself behaves as a δ selective antagonist [2]and even more significantly introduction of Tic in the second position of the sequence converts enkephalin, a non‐selective agonist, and dermorphin (a μ selective agonist) into δ selective antagonists [5]. The view of a specific `antagonist message' was subsequently substantiated by the discovery of ultraselective δ antagonists containing the Tyr(Me) 2 ‐Tic message [4, 6]and by the design of a rigid antagonist lacking the basic charge of tyramine [7].…”

Bioactivity of New μ and δ Opioid Peptides

“…On the other hand, minima (III) and to a lesser extent (II) have a fairly good overlay with the molecular model of CNX whereas minima (I) and to a lesser (II) have a fairly good overlay with the molecular model of ICI 199441. The fact that the fit is no perfect, particularly at the basic nitrogen and the second aromatic ring (distinct from that of tyramine), hints that high agonist activity may be prevented whereas antagonism is still likely [51].…”

“…In fact Tyr-Tic-Phe-NH 2 itself behaves as a selective antagonists [43] and even more significantly introduction of Tic in the second position of the sequence converts enkephalin, a non-selective agonist, and dermorphin (a -selec- Table 3 tive agonist) into selective antagonists [49]. The view of a specific "antagonist message" was subsequently substantiated by the discovery of ultraselective antagonists containing the Tyr-(Me) 2 -Tic message [46,50] and by the design of a rigid antagonist lacking the basic charge of tyramine [51].…”