79985-48-1Relevant articles and documents
Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on κ receptor selectivity and potency
Lung, Feng-Di T.,Meyer,Lou, Bih-Show,Xiang, Li,Li, Guigen,Davis, Peg,De Leon, Irene A.,Yamamura, Henry I.,Porreca, Frank,Hruby, Victor J.
, p. 2456 - 2460 (1996)
Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at κ receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1-11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central κ opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for κ vs μ and κ vs δ receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for κ opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for κ, μ, and δ opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the κ receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the κ receptor.
[2′,6′-dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group: Potent and selective κ opioid antagonists
Lu,Nguyen,Weltrowska,Berezowska,Lemieux,Chung,Schiller
, p. 3048 - 3053 (2001)
Recent studies showed that dermorphin and enkephalin analogues containing two methyl groups at the 2′,6′-positions of the Tyr1 aromatic ring and lacking an N-terminal amino group were moderately potent δ and μ opioid antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containing an N-terminal 2′,6′-dimethyltyrosine (Dmt) residue may represent a general way to convert them into antagonists. In an attempt to develop dynorphin A (Dyn A)-derived κ opioid antagonists, we prepared analogues of [Dmt1]Dyn A(1-11)-NH2 (1), in which the N-terminal amino group was either omitted or replaced with a methyl group. This was achieved by replacement of Tyr1 with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl) propanoic acid [(2S)-Mdp]. Compounds were tested in the guinea pig ileum and mouse vas deferens bioassays and in rat and guinea pig brain membrane receptor binding assays. All analogues turned out to be potent κ antagonists against Dyn A(1-13) and the non-peptide agonist U50,488 and showed only weak μ and δ antagonist activity. The most potent and most selective κ antagonist of the series was [(2S)-Mdp1]Dyn A(1-11)-NH2 (5, dynantin), which showed subnanomolar κ antagonist potency against Dyn A(1-13) and very high κ selectivity both in terms of its Ke values determined against κ, μ, and δ agonists and in terms of its ratios of κ, μ, and δ receptor binding affinity constants. Dynantin is the first potent and selective Dyn A-derived κ antagonist known and may complement the non-peptide κ antagonists norbinaltorphimine and GNTI as a pharmacological tool in opioid research.
Design, Synthesis, and Biological Properties of Highly Potent Cyclic Dynorphin A Analogues. Analogues Cyclized between Positions 5 and 11
Meyer, Jean-Philippe,Collins, Nathan,Lung, Feng-Di,Davis, Peg,Zalewska, Teresa,et al.
, p. 3910 - 3917 (2007/10/02)
We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand.Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the κ and μ receptors of the central over the peripheral nervous systems.In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides.In addition, Dyn A1-11-NH2, 5>Dyn A1-11-NH2, and 11>Dyn A1-11-NH2 were synthesized as standards.Several of these cyclic analogues, especially c5,D-Cys11>Dyn A1-11-NH2, c5,L- or D-Pen11>Dyn A1-11-NH2, c5,L-Pen11>Dyn A1-11-NH2 and c5,L- or D-Cys11>Dyn A1-11-NH2, retained the same affinity and selectivity (vs the μ and δ receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB).These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously.In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at κ opioid receptors.The results obtained in the GPB suggest that requirements for binding are not the same for the κ, μ, or δ central receptors.
