Photolabile opioid derivatives of D-Ala2-Leu5-enkephalin and their interactions with the opiate receptor.
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Cited by 20 publications
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Synthesis and Properties of a 2‐Diazohistidine Derivative: A New Photoactivatable Aromatic Amino‐Acid Analog
Na[(tert-Butoxy)carbonyl]-2-diazo-~-histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1,2-amino-~-histidine derivative 3, was best isolated and characterized as 2-amino-Nr-[(tert-butoxy)carbonyl]-~T-tosyl-~-histidine methyl ester (4). Selective deprotections of 4 (N"-Boc, N'-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-Nr-tosyl-~-histidine methyl ester ( 5 ) with N-[(tert-butoxy)cdrbonyl]-L-alanine and N'-[(rert-buto~y)carbonyl]-N~-tosyl-~-histidine (6) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-lH-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.Introduction. -The discovery of numerous peptides involved in the recognition and modulation of hormone or neuromediator receptors stimulated the design and the synthesis of peptide analogs in order to study ligand-receptor interactions. Among these probes, photoactivatable structures were conceived to label irreversibly the receptor at a target binding site by means of photoaffinity labelling experiments [l]. Two major results are expected from this approach, either to identify and characterize an unknown receptor or to define at a molecular level the ligand-receptor interactions.The synthesis of photoactivatable peptides was first conceived by tagging a photosensitive group to an existing peptide. Most of the described examples used electrophilic reagents bearing an arylazido or a benzophenone moiety, the coupling of the reagent to the peptide being generally directed towards the C-terminal [2] or towards nucleophilic residues existing on the peptide such as the primary amino group of a lysine side chain [3]. Besides the problem of selectivity of modification which can arise, the major limitation of this method is the consequent structural changes caused by the attachment of the photosensitive group on the natural ligand which often induces a loss in binding affinity. The design of a photosensitive amino-acid analog structurally related to a natural amino acid and which could be incorporated in the peptide during the synthesis (solid phase or in solution), would overcome the above mentioned limitations. As such, the 4'-azidophenylalanine derivative [4] has been developed and used as a substitute for phenylalanine in several peptides [5]. The syntheses of those peptides used a 4'-nitrophenylalanine precursor which was subsequently transformed to the corresponding 4'-azido derivative.
Synthesis and Properties of a 2‐Diazohistidine Derivative: A New Photoactivatable Aromatic Amino‐Acid Analog
Na[(tert-Butoxy)carbonyl]-2-diazo-~-histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1,2-amino-~-histidine derivative 3, was best isolated and characterized as 2-amino-Nr-[(tert-butoxy)carbonyl]-~T-tosyl-~-histidine methyl ester (4). Selective deprotections of 4 (N"-Boc, N'-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-Nr-tosyl-~-histidine methyl ester ( 5 ) with N-[(tert-butoxy)cdrbonyl]-L-alanine and N'-[(rert-buto~y)carbonyl]-N~-tosyl-~-histidine (6) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-lH-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.Introduction. -The discovery of numerous peptides involved in the recognition and modulation of hormone or neuromediator receptors stimulated the design and the synthesis of peptide analogs in order to study ligand-receptor interactions. Among these probes, photoactivatable structures were conceived to label irreversibly the receptor at a target binding site by means of photoaffinity labelling experiments [l]. Two major results are expected from this approach, either to identify and characterize an unknown receptor or to define at a molecular level the ligand-receptor interactions.The synthesis of photoactivatable peptides was first conceived by tagging a photosensitive group to an existing peptide. Most of the described examples used electrophilic reagents bearing an arylazido or a benzophenone moiety, the coupling of the reagent to the peptide being generally directed towards the C-terminal [2] or towards nucleophilic residues existing on the peptide such as the primary amino group of a lysine side chain [3]. Besides the problem of selectivity of modification which can arise, the major limitation of this method is the consequent structural changes caused by the attachment of the photosensitive group on the natural ligand which often induces a loss in binding affinity. The design of a photosensitive amino-acid analog structurally related to a natural amino acid and which could be incorporated in the peptide during the synthesis (solid phase or in solution), would overcome the above mentioned limitations. As such, the 4'-azidophenylalanine derivative [4] has been developed and used as a substitute for phenylalanine in several peptides [5]. The syntheses of those peptides used a 4'-nitrophenylalanine precursor which was subsequently transformed to the corresponding 4'-azido derivative.
Selective Monoderivatization of Propane‐1,3‐diamine with Acid Chlorides: ‘Hexahydropyrimidine method’ vs. statistic methods
The selective N-monoderivatization of propane-I ,3-diamine (5) with carbonyl and sulfonyl chlorides via 2-phenylhexahydropyrimidine (6) was compared with the direct statistic monoderivatization. It was found that, under optimized conditions, both methods are competitive to one another, depending, however, strongly on the reactivity of the electrophile used. The 'hexahydropyrimidine method' is more reliable with respect to yields, which are moderate but invariably between 54 and 69%, whereas the 'statistic method' leads in certain cases to exceptionally high yields (up to 96%), in others, however, almost none.Introduction. -Naturally occurring polyamines have been shown to be important in living cells. For instance, they show high affinity towards nucleic acids and provide numerous effects on nucleic-acid biosynthesis and metabolism [ 11. Not only the polyamines but also natural and artificial polyamine derivatives display [2-51 various physiological activities. Polyamines are also used as spacer elements for the interconnection of receptor pharmacophores to form unsymmetrical bivalent ligands [6] or for the linkage of pharmacophores with alkylating or photolabile groups to generate affinity labels [7]. For the chemical synthesis of such physiologically interesting derivatives, polyamines in their terminally N-monoprotected form represent the starting material of choice [S-141. Preparation of these compounds, however, is not facile [3] [15], not even in the simplest cases of the synthesis of N-monoderivatized alkane-a,w-diamines.In [16], we have reported that N-substituted propane-l,3-diamines can efficiently be monoderivatized at the secondary N-atom using a hexahydropyrimidine intermediate of type 1. We have proposed that heterocycles of type 1 rapidly undergo ring opening to imino-amino species of the type 2, which, in turn, react with eletrophiles to compounds of type 3. These gave, after hydrolysis, rise to the corresponding diamine derivatives of type 4 (Scheme 1). The hexahydropyrimidine moieties acted in this reaction sequence as the precursors of the protecting imino groups for the aliphatic primary amines. Since this procedure should invariantly lead to analogous products starting from hexahydropyrimidines that are not substituted at the N-atoms, we expected the hexahydropyrimidine protocol for monoderivatization of propane-l,3-diamine (5) to be a competitive alternative to the statistic methods used so far [17-221.We describe in this paper our results obtained with 2-phenylhexahydropyrimidine as the precursor of N-monofunctionalized propane-l,3-diamines 12 a-d (Scheme 2) and compare our findings to results of an optimized statistic derivatization method.
In a previous work, the synthesis of [3H] Tyr‐D‐Thr‐Gly‐Phe‐Leu‐Thr (DTLET), a highly selective probe for δ opioid receptors has been described. More recently, Az‐DTLET (Tyr‐D‐Thr‐Gly‐Phe (pN3)‐Leu‐Thr) has been shown to be a specific and irreversible photoaffinity ligand for δ opioid sites. In the present paper, we reported the synthesis of the 3,5 dibromotyrosyl 4′‐amino‐3′,5′ diiodophenylalanyl precursor of [3H] Az‐DTLET. Reductive tritiation by exchange with 3H2 followed by the introduction of the azido group leads to the labelled azido analog of enkephalin with specific activity of 50 Ci/mmole. This compound is now used to characterize the subunits of opioid δ receptors and to visualize these targets in the brain by electron microscopy.
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