Development of Receptor-Selective Opioid Peptide Analogs as Pharmacologic Tools and as Potential Drugs

Schiller, Peter W.

doi:10.1007/978-3-642-77460-7_27

Cited by 23 publications

(18 citation statements)

References 81 publications

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“…Because of the potential differences in interactions of peptides and nonpeptides with the same receptors, peptide‐based affinity labels could provide complementary pharmacological information to nonpeptide affinity labels (5). The peptide‐based affinity labels reported to date are mainly photoaffinity labels such as azido‐containing derivatives of DAMGO, DTLET, and DPDPE (6). The use of photoaffinity labels has been limited because opioid receptors are susceptible to inactivation by the UV irradiation used to generate the reactive intermediates.…”

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Dermorphin‐based potential affinity labels for µ‐opioid receptors*

Choi

Murray

Aldrich

2003

The Journal of Peptide Research

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Dermorphin and [Lys7]dermorphin, selective micro -opioid receptor ligands originating from amphibian skin, have been modified with various electrophiles in either the 'message' or 'address' sequences as potential peptide-based affinity labels for micro -receptors. Introduction of the electrophilic isothiocyanate and bromoacetamide groups on the para position of Phe3 and Phe5 was accomplished by incorporating Fmoc-Phe(p-NHAlloc) into the peptide followed by selective deprotection and modification. The corresponding amine-containing peptides were also prepared. The pure peptides were evaluated in radioligand binding experiments using Chinese hamster ovary (CHO) cells expressing micro - and delta-opioid receptors. In dermorphin, introduction of the electrophilic groups in the 'message' domain lowered the binding affinity by > 1000-fold; only [Phe(p-NH2)3]dermorphin retained nanomolar affinity for micro -receptors. Modifications in the 'address' region of both dermorphin and [Lys7]dermorphin were relatively well tolerated. In particular, [Phe(p-NH2)5,Lys7]dermorphin showed similar affinity to dermorphin, with almost 2-fold higher selectivity for micro -receptors. [Phe(p-NHCOCH2Br)5]- and [Phe(p-NHCOCH2Br)5,Lys7]dermorphin exhibited relatively high affinity (IC50 = 27.7 and 15.1 nm, respectively) for micro -receptors. However, neither of these peptides inhibited [3H]DAMGO binding in a wash-resistant manner.

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Dermorphin‐based potential affinity labels for µ‐opioid receptors*

Choi

Murray

Aldrich

2003

The Journal of Peptide Research

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“…In recent years, significant advances have been made in opioid research, particularly with respect to the synthesis of peptides with high affinity and selectivity for the different types (µ, δ, κ) of opioid receptors (1–4). These opioid receptor‐specific peptides have unique pharmacological properties that warrant their development as therapeutic agents.…”

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Synthesis and evaluation of the physicochemical properties of esterase‐sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers

Wang

Nimkar

Wang

et al. 1999

The Journal of Peptide Research

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In an attempt to improve the membrane permeabilities of opioid peptides, we have synthesized cyclic prodrugs of [Leu5]-enkephalin and DADLE using a coumarinic acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid- and phenylpropionic acid-based cyclic prodrugs followed similar strategies. Key intermediates were the compounds with the C-terminal amino acids of opioid peptides (L-Leu, [Leu5]-enkephalin; D-Leu, DADLE) attached to the phenol hydroxyl group and the remaining amino acids of the peptide linked via the N-terminal amino acid (L-Tyr) attached to the carboxylic acid groups of the prodrug moieties (coumarinic acid or propionic acid). Cyclization of these linear precursors gave the cyclic prodrugs in 30-50% yields. These cyclic prodrugs exhibited excellent transcellular permeation characteristics across Caco-2 cell monolayers, an in vitro model of the intestinal mucosa. To correlate the cellular permeabilities of these cyclic prodrugs with their physicochemical properties, we calculated their Stokes-Einstein molecular radii from their diffusion coefficients which were determined by NMR and we determined their membrane interaction potentials using immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs exhibited molecular radii similar to those of the parent compounds, [Leu5]-enkephalin and DADLE. However, these cyclic prodrugs were shown to have much higher membrane interaction potentials than their corresponding opioid peptides. Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently due to the alteration of their lipophilicity and hydrogen bonding potential, but not their molecular sizes.

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“…Early peptide-based affinity labels for opioid receptors were mainly photoaffinity labels containing Phe( p -N 3 ) (see (Takemori and Portoghese, 1985; Schiller, 1993; Aldrich and Vigil-Cruz, 2003) for reviews). However, the use of photoaffinity labels for opioid receptors has been limited because these receptors are susceptible to inactivation by UV irradiation (Glasel and Venn, 1981).…”

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confidence: 99%

Solid Phase Synthesis and Application of Labeled Peptide Derivatives: Probes of Receptor-Opioid Peptide Interactions

Aldrich

Kumar

Dattachowdhury

et al. 2008

Int J Pept Res Ther

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Solid phase synthetic methodology has been developed in our laboratory to incorporate an affinity label (a reactive functionality such as isothiocyanate or bromoacetamide) into peptides (Leelasvatanakij, L. and Aldrich, J. V. (2000) J. Peptide Res. 56, 80), and we have used this synthetic strategy to prepare affinity label derivatives of a variety of opioid peptides. To date side reactions have been detected only in two cases, both involving intramolecular cyclization. We have identified several peptide-based affinity labels for δ opioid receptors that exhibit wash-resistant inhibition of binding to these receptors and are valuable pharmacological tools to study opioid receptors. Even in cases where the peptide derivatives do not bind covalently to their target receptor, studying their binding has revealed subtle differences in receptor interactions with particular opioid peptide residues, especially Phe residues in the N-terminal "message" sequences. Solid phase synthetic methodology for the incorporation of other labels (e.g. biotin) into the C-terminus of peptides has also been developed in our laboratory (Kumar, V. and Aldrich, J. V. (2003) Org. Lett. 5, 613). These two synthetic approaches have been combined to prepare peptides containing multiple labels that can be used as tools to study peptide ligand-receptor interactions. These solid phase synthetic methodologies are versatile strategies that are applicable to the preparation of labeled peptides for a variety of targets in addition to opioid receptors.

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Development of Receptor-Selective Opioid Peptide Analogs as Pharmacologic Tools and as Potential Drugs

Cited by 23 publications

References 81 publications

Dermorphin‐based potential affinity labels for µ‐opioid receptors*

Dermorphin‐based potential affinity labels for µ‐opioid receptors*

Synthesis and evaluation of the physicochemical properties of esterase‐sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers

Solid Phase Synthesis and Application of Labeled Peptide Derivatives: Probes of Receptor-Opioid Peptide Interactions

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