Preparation and opioid activity of analogs of the analgesic dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide

Chandrakumar, Nizal S.; Yonan, Peter K.; Stapelfeld, Awilda; Savage, Michael A.; Rorbacher, Elaine; Contreras, Patricia C.; Hammond, Donna L.

doi:10.1021/jm00080a005

Cited by 42 publications

(25 citation statements)

References 2 publications

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“…Although a number of high-yielding procedures are available for the selective acylation of simple a-or b-aminoalcohols, [13] literature reports on the selective acylation of a,b-diaminoalcohols are scarce. [14] Initial attempts to couple 1 with the substituted cinnamic acid 3'-cyano-6'-methoxycinnamic acid in the presence of several activating agents such as acid chlorides, carbodiimides, or uronium and phosphonium reagents, delivered low yields. The reaction outcomes were complicated by the presence of significant amounts of N,O-diacylated by-product.…”

Section: Proton-mediated Chemoselectivitymentioning

confidence: 99%

“…[22] In a marked improvement to synthetic efficiency, Enick, Hamilton, and co-workers showed that protection and deprotection can be circumvented by performing the reaction under acidic conditions. [23] In the presence of AcOH, the nucleophilicity of the amine is attenuated, thereby allowing the acylation of all five hydroxy groups of d-glucamine (14) to occur in one step, thus affording 15 in 72 % yield (Scheme 7).…”

Section: Proton-mediated Chemoselectivitymentioning

confidence: 99%

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Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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Achieving high levels of chemoselectivity has been the Achilles' heel of chemical synthesis. The excitement generated by the successful realization of chemoselective strategies underscores the painstaking efforts to define a set of conditions conducive to selection among the available reaction pathways. We discuss in this Review various aspects of chemoselectivity that have been addressed in a range of synthetic methods over the past decade. We have focused on the proposed mechanistic basis of the reactions under consideration in an attempt to categorize them and highlight the key concepts that have been emerging on the basis of these studies. Our overview of recent advances in chemoselective processes suggests that significant progress has been made, but a lot of challenges lie ahead.

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Section: Proton-mediated Chemoselectivitymentioning

confidence: 99%

Section: Proton-mediated Chemoselectivitymentioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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“…Recent structure-activity studies have shown that introduction of the artificial amino acid 2Ј,6Ј-dimethyltyrosine (Dmt) in place of the N-terminal Tyr residue is a promising way to greatly enhance receptor affinity and functional potency. [2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II.…”

mentioning

confidence: 99%

2',6'-Dimethylphenylalanine (Dmp) Can Mimic the N-Terminal Tyr in Opioid Peptides

Sasaki

Ariizumi

et al. 2004

Biological & Pharmaceutical Bulletin

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In opioid peptides, the N-terminal Tyr and the Phe at position 3 or 4 are aromatic residues that are necessary for the opioid activity. Recent structure-activity studies have shown that introduction of the artificial amino acid 2Ј,6Ј-dimethyltyrosine (Dmt) in place of the N-terminal Tyr residue is a promising way to greatly enhance receptor affinity and functional potency. [2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II. 16) We also demonstrated that Dmp can be substituted for the N-terminal Tyr residue in the m receptor-selective agonists YRFB 14) and endomorphin 2 15) without a substantial decrease in m receptor affinity and selectivity. In particular, the Dmp 1 -YRFB had somewhat higher m receptor affinity than the parent peptide, although its in vitro bioactivity was slightly lower.14) These findings are interesting because the Dmp 1 -peptides lack a phenolic hydroxyl group at the N-terminal side chain. More importantly, these Dmp 1 -analogues had high m receptor selectivity. These findings contrast with the effects of Dmt 1 -substitution. In the present study, we report further analogues of the d opioid receptor-selective ligands, deltorphin II (DLT: Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH 2 ) and Leu-enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu), containing Dmp or Dmt at position 1. MATERIALS AND METHODSPeptide Synthesis Peptides were generated by solid phase synthesis using a DIC/HOBt-mediated Fmoc strategy, as previously described.15) Fmoc-Dmp or Boc-Dmt used was prepared by the method reported previously. 13,17) For the synthesis of DLT analogues (1, 2), an N-terminal Dmp residue was incorporated using Fmoc-Dmp racemate.17) Cleavage of the peptides from the resin was carried out by treatment with TFA-phenol (95 : 5) at room temperature for 1 h. The diastereoisomeric peptides (1, 2) were separated using medium-pressure HPLC, as described previously.18) The absolute configuration of the Dmp residue in 1 and 2 was determined by the analysis of the HCl hydrolysate of the peptides using chiral TLC plates (CH 3 CN : MeOH : H 2 Oϭ4 : 1 : 1). 17)Analytical HPLC (YMC-Pack ODS-AM-302 column, 150ϫ 4.6 mm) demonstrated that the purity of all peptides was Ͼ96%. All analogues reported here gave satisfactory FAB-MS and amino acid analytical data (Table 1).Receptor Binding Assay The opioid receptor binding assays were performed as described previously. In Vitro Bioactivity Assay The in vitro biological activities were evaluated using guinea pig ileum (GPI) and mouse vas deferens (MVD) tissues, as detailed previously.15) Isolated longitudinal muscle strips from Hartley strain guinea pig (250-300 g) and vas deferens from ddY strain mice (25-35 g) ...

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“…The effectiveness of Dmt to modify peptide behavior was demonstrated by the drastic increases in δ-or µ-receptor affinity. Substitutions of Dmt in place of Tyr at the N-terminus of diverse groups of opioid peptides produced a broad range of activities [87][88][89][90][91][92]. A δ-agonist deltorphin-II 81 acquired high µ-bioactivity [93], while the κ-agonist dynorphin(1-11)NH 2 became a κ-antagonist 83 [94].…”

Section: Methylation Of the Aromatic Rings Of Tyrosine And Phenylalaninementioning

confidence: 99%

Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

Janecka¹,

Kruszyński

2005

CMC

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The discovery of endogenous opioid peptides with their limited receptor selectivity more than two decades ago implicated their involvement in analgesia and initiated efforts to understand the molecular mechanisms underlying their action. Opioid peptides mediate their physiological and pharmacological effects through three major opioid receptor types (mu, delta, kappa), but the role of each of these receptors is not easy to distinguish. There has therefore, been an increasing need for potent and selective agonists and antagonists in this area. The incorporation of conformational constraints into analogs of biologically active peptides is a well-known approach for enhancing receptor selectivity and modulating efficacy. Conformational restriction has proven a valuable means for assessing disparities between the peptide binding characteristics at each of the opioid receptor types, since peptide analogs designed with appropriate conformational constraints possess the ability to adopt the conformation required for interaction at one receptor type but not another. In efforts to obtain better conformational integrity various conformationally restricted analogs of endogenous opioid peptides have been developed. In this paper we review the development of opioid analogs whose conformation was restricted either globally through different types of cyclization (such as amide bond formation, disulfide and monosulfide bridges, carbonyl and amine bridges) or locally, through incorporation of side-chain conformational constraints at a specific amino acid residue by synthesizing cyclic amino acids or constraining torsion angles by suitable substitutions. These two approaches have led to the development of potent and very selective agonists and antagonists at all three opioid receptor types.

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Preparation and opioid activity of analogs of the analgesic dipeptide 2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide

Cited by 42 publications

References 2 publications

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2',6'-Dimethylphenylalanine (Dmp) Can Mimic the N-Terminal Tyr in Opioid Peptides

Conformationally Restricted Peptides as Tools in Opioid Receptor Studies

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