Non-peptide δ opioid agonists and antagonists

Dondio, Giulio; Ronzoni, Silvano; Petrillo, Paola

doi:10.1517/13543776.7.10.1075

Cited by 57 publications

(50 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, reaction of 14 with LiHMDS or LDA failed to give the bicyclic ketone 17. Surprisingly, the reaction of 14 with phenylmagnesium bromide led to the bicyclic ketone in 10 % yield and the allyl derivative 18 (15 %) which results from a [3,3]-sigmatropic rearrangement. Careful analysis of the 1 H NMR spectrum of the LDA experiment proved, that 18 had also been formed in this experiment.…”

Section: Chemistrymentioning

confidence: 99%

“…High affinity κ agonists also display analgesic effects δ agonists also induce strong analgesia with no or little liability to induce the typical side effects of μ and κ agonists. Moreover, they potentiate the analgesic effect of morphine in subanalgesic doses [3]. Because of their antinociceptive potency and the lack of side effects δ agonists are considered as safe analgesics [3,4].…”

mentioning

confidence: 99%

“…Moreover, they potentiate the analgesic effect of morphine in subanalgesic doses [3]. Because of their antinociceptive potency and the lack of side effects δ agonists are considered as safe analgesics [3,4]. In addition to their analgesic activity δ agonists possess further pharmacological effects e.g.…”

mentioning

confidence: 99%

“…TAN 67) and piperazine based compounds (e.g. SNC 80 (1), BW 373U86 (2)) [3, 4]. Intensive structure activity relationship studies based on SNC 80 (1) showed that the carboxamido moiety [3] and a cyclic amine [5] are required for strong δ receptor interaction.…”

mentioning

confidence: 99%

“…SNC 80 (1), BW 373U86 (2)) [3, 4]. Intensive structure activity relationship studies based on SNC 80 (1) showed that the carboxamido moiety [3] and a cyclic amine [5] are required for strong δ receptor interaction. Removal of the piperazine methyl groups decreased the δ receptor affinity [6] and replacement of the Nallyl moiety by a proton or by alkyl or other alkenyl residues resulted in less potent δ agonists [6].…”

mentioning

confidence: 99%

See 4 more Smart Citations

Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80

Englberger

Wünsch²

2005

Archiv der Pharmazie

View full text Add to dashboard Cite

In order to find novel delta opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead compound SNC 80 (1) was dissected and the phenyl residues were attached to different positions of the 6,8-diazabicyclo[3.2.2]nonane core system (4). The position of the carboxamido group, the stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The resulting compounds were compared with the four energetically most favourable conformations of SNC 80 by a multifit analysis. These calculations led to the structures 5-10, which fit best to SNC 80. Herein the synthesis of one of these compounds (9) is described. Starting from (S)-glutamate two alternative routes are detailed to obtain the key intermediate 14. A variation of the Dieckmann cyclization, which uses trapping of the first cyclization product with ClSiMe(3) provided the mixed acetal 20, which was carefully hydrolyzed to yield the bicyclic ketone 17. Stereoselective addition of phenylmagnesium bromide, dehydration, LiAlH(4) reduction and exchange of the N-6 residue afforded the designed compound 9. The affinities of 9 towards delta, mu, kappa and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.

show abstract

Section: Chemistrymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80

Englberger

Wünsch²

2005

Archiv der Pharmazie

View full text Add to dashboard Cite

show abstract

Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

View full text Add to dashboard Cite

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.

show abstract

Opioid Receptor Ligands

McCurdy

Prisinzano

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

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.

show abstract

Non-peptide δ opioid agonists and antagonists

Cited by 57 publications

References 61 publications

Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80

Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80

Narcotic Analgesics

Opioid Receptor Ligands

Contact Info

Product

Resources

About