Synthesis of the diastereomers of ?-Me-Tyr and ?-Me-Phe and their effect on the biological properties of the delta opioid receptor antagonist TIPP

Mannekens, Els; Tourwé, Dirk; Vanderstichele, Sylvia; Diem, Trang Nguyen Thi; Tóth, Géza; Péter, Antal; Chung, Nga N.; Schiller, Peter P.W.

doi:10.1007/bf00119150

Cited by 6 publications

(2 citation statements)

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“…[28][29][30] From the resulting 70/30 mixture of E-and Z-oxazolone, the E isomer was easily isolated by crystallization. 31 The E-oxazolone can be isomerized to the Z isomer in pyridine. 28 Further catalytic hydrogenation and subsequent deprotection steps afforded the erythro-β-MeTyr and threo-β-MeTyr racemates.…”

Section: Resultsmentioning

confidence: 99%

“…The β-MeTic isomers were prepared by a Pictet−Spengler reaction, , starting from pure erythro- or threo -β-MePhe. For the preparation of the β-MeTyr stereoisomers, an Erlenmeyer condensation between 4-methoxyacetophenone and hippuric acid was performed using a modification of the previously described protocol (Scheme ). − From the resulting 70/30 mixture of E - and Z -oxazolone, the E isomer was easily isolated by crystallization . The E -oxazolone can be isomerized to the Z isomer in pyridine .…”

Section: Resultsmentioning

confidence: 99%

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Side Chain Methyl Substitution in the δ-Opioid Receptor Antagonist TIPP Has an Important Effect on the Activity Profile

et al. 1998

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The delta-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding beta-methyl amino acid. The potency and selectivity (delta- vs mu- and kappa-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing L-beta-methyl amino acids the influence on delta-receptor affinity and on delta-antagonist potency is limited, the [(2S,3R)-beta-MePhe3]TIPP-OH analogue being among the most potent delta-antagonists reported. In the D-beta-methyl amino acid series, the [D-beta-MeTic2] analogues are delta-selective antagonists whereas [D-Tic2]TIPP-NH2 is a delta-agonist. NMR studies did not indicate any influence of the beta-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-beta-MePhe3]TIPP-NH2 is a potent delta-agonist, its C-terminal carboxylic acid analogue being more delta-selective but displaying partial agonism in both the delta- and mu-bioassay. These results constitute further examples of a profound influence of beta-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Side Chain Methyl Substitution in the δ-Opioid Receptor Antagonist TIPP Has an Important Effect on the Activity Profile

et al. 1998

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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Opioid Receptor Ligands

McCurdy

Prisinzano

2010

Burger's Medicinal Chemistry and Drug Discovery

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Opioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.

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Synthesis of the diastereomers of ?-Me-Tyr and ?-Me-Phe and their effect on the biological properties of the delta opioid receptor antagonist TIPP

Cited by 6 publications

References 7 publications

Side Chain Methyl Substitution in the δ-Opioid Receptor Antagonist TIPP Has an Important Effect on the Activity Profile

Side Chain Methyl Substitution in the δ-Opioid Receptor Antagonist TIPP Has an Important Effect on the Activity Profile

Narcotic Analgesics

Opioid Receptor Ligands

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