2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products.

Background:Diclofenac is a proven, commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been shown to be effective in treating a variety of acute and chronic pain and inflammatory conditions. As with all NSAIDs, diclofenac exerts its action via inhibition of prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency. However, extensive research shows the pharmacologic activity of diclofenac goes beyond COX inhibition, and includes multimodal and, in some instances, novel mechanisms of action (MOA).Data sources:Literature retrieval was performed through PubMed/MEDLINE (through May 2009) using combinations of the terms diclofenac, NSAID, mechanism of action, COX-1, COX-2, and pharmacology. Reference citations resulting from publications identified in the literature search were reviewed when appropriate.Methods:This article reviews the established, putative,...

Diclofenac: an update on its mechanism of action and safety profile

G protein-coupled receptors (GPCRs) constitute the largest family of cellular receptors involved in signal transduction. A review is given of the voluminous structural and/or activity evidence in support of a ligand turn shape being the likely recognition domain in GPCR-binding domains of all of these ligands. In the absence of structurally defined GPCR-ligand complexes, solution or solid-state structures are analyzed for a variety of GPCR-binding ligands alone, including (i) peptide and protein hormone ligands, (ii) bioactive peptide fragments, (iii) cyclic peptides, often analogous of protein segments, (iv) peptidomimetic antagonists with a conformational bias enforced by the presence of turn-inducing constraints. Examples of small cyclic peptidomimetics for naturally occurring GPCR-binding small peptides are also covered, including, somatosatin (14 residues), melanocyte-stimulating hormone (13), oxytocin (9), vasopressin (9), substance P (11), bradykinin (9), opiod peptides, and small fragments of proteins.

Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure.

Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK1 and CCK2. Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK1 and CCK2 antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK1 and CCK2 antagonist. CCK1 antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK2 antagonists might have application for the treatment of gastric acid secretion and anxiety disorders. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 559–605, 2003

Cholecystokinin antagonists: Pharmacological and therapeutic potential

A practical sequence involving three consecutive palladium(0)-catalyzed reactions has been developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors 10 and 11a-k are generated in one step by chemoselective Stille cross-coupling of 2'-triflato-(Z)-2-stannyl-2-butenanilide 9 with aryl or heteroaryl iodides. The pivotal catalytic asymmetric Heck cyclization step of this sequence takes place in high yield and with high enantioselectivity (71-98% ee) with the Pd-BINAP catalyst derived from Pd(OAc)(2) to construct oxindoles containing a diaryl-substituted all-carbon quaternary carbon center. A wide variety of aryl and heteroaryl substituents, including ones of considerable steric bulk, can be introduced at C3 of oxindoles in this way (Table 4). The only limitations encountered to date are aryl substituents containing ortho nitro or basic amine functionalities and the bulky N-alkyl-7-oxindolyl group. Asymmetric Heck cyclization of butenalide 22 having an o-(N-acetyl-N-benzylamino)phenyl substituent at C2 provided a approximately 1:1 mixture of amide atropisomers 23 and 24 in high yield and high enantioselectivity. These atropisomers are formed directly upon Heck cyclization of 22 at 80 degrees C, as they interconvert thermally to only a small extent at this temperature.

Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular heck reactions.

A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar affinities.

Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives.

Objectives: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4′-hydroxyaceclofenac, in comparison with diclofenac, another metabolite, on cyclooxygenases activity as well as interleukin-1β, -6 and -8, nitric oxide, and prostaglandin E2 production by human osteoarthritic and normal articular chondrocytes.
Methods: Enzymatically isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1β (IL-1β) or lipopolysacharride (LPS) and with or without increased amounts (1 to 30 μM) of aceclofenac or metabolites. The production of different cytokines was measured by Enzyme Amplified Sensitivity Immunoassays (EASIA). Prostaglandin E2 was quantified by a specific radioimmunoassay. Nitrite and nitrate concentrations in the culture supernatants were determined by spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2, inducible NO synthase and IL-1β gene expression were quantified by reverse transcription of mRNA followed by real time and quantitative polymerase chain reaction. Finally, cyclooxygenase inhibitory potency of the drugs was also tested in both a cell-free system using purified ovine cyclooxygenase-1 and -2 (COX-1 and COX-2) and at a cellular level using human whole blood assay.
Results: We have demonstrated that aceclofenac, 4′-hydroxyaceclofenac and diclofenac significantly decreased interleukin-6 production at concentrations ranged among 1 to 30 μM and fully blocked prostaglandin E2 synthesis by IL-1β- or LPS-stimulated human chondrocytes. Aceclofenac and diclofenac had no effect on interleukin-8 production while 4′-hydroxyaceclofenac slightly decreased this parameter at the highest dose (30 μM). Aceclofenac was without effect on IL-1β- or LPS-stimulated nitric oxide production. At 30 μM, 4′-hydroxyaceclofenac inhibited both IL-1β or LPS-stimulated nitric oxide production while diclofenac inhibited only the LPS-stimulated production. Finally, at 30 μM, the three drugs significantly decreased IL-1β mRNA. In the whole blood test, aceclofenac and 4′-hydroxyaceclofenac weakly inhibited COX-1 with IC50 values superior to 100 μM, but decreased by 50% COX-2 activity at the concentration of 0.77 and 36 μM, respectively. Diclofenac strongly inhibited both COX-1 and COX-2 with IC50 values of 0.6 and 0.04 μM, respectively. On the other hand, aceclofenac and diclofenac weakly inhibited purified ovine cyclooxygenases with IC50 values superior to 100 μM, whereas 4′-hydroxyaceclofenac was without effect.
Conclusions: These results suggest that aceclofenac actions are multifactorial and that metabolites could contribute to its anti-inflammatory actions.

In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators.

During the last few years, cholecystokinin (CCK) has emerged as an important hormone This polypeptide has been located either in peripheral tissues such as the gastro-intestinal tract and the pancreas as well as in the central nervous system High affinity CCK receptors are divided in two main subtypes: the CCK-A (A for (A for "alimentary") and the CCK-B (B for "brain") receptors The latters are currently associated with the gastrin receptors Since CCK is involved in many different biological processes such as gut function, digestive processes, control of feeding behaviour and neurotransmitter release, the therapeutical potential of cholecystokinin receptor ligands seems to be extremely broad and promising Several families of CCK receptor ligands (peptides, peptidomimetics, peptoids or non-peptides) were prepared during the last twenty years The main goal of these researches was to improve agonistic or antagonistic potency but also to find selective compounds for a specific CCK receptor subtype This review presents the recent developments (since 1995) in the chemistry of CCK receptor ligands

Recent advances in the chemistry of cholecystokinin receptor ligands (agonists and antagonists).

While neuroleptic therapy with classical compounds has frequently been associated with extrapyramidal side effects, clozapine has revealed an interesting antipsychotic profile without producing any clearcut motor side effects. However, some adverse reactions remained that stimulated the search for improved antipsychotic agents. The aim of this study was to characterize the behavioural and neurochemical profiles of typical neuroleptics (chlorpromazine, haloperidol), clozapine, and four newly synthesized clozapine-analogues. Affinity for dopaminergic (D1,D2), serotonergic (5-HT(2)) and cholinergic (muscarinic) receptors were measured and the ratios of these different binding affinities were determined and correlated with the behavioural effects of the drugs in a complex temporal regulation task in the dog. The four clozapine-analogues showed most of the behavioural characteristics previously described for neuroleptics and their neurochemical profile, particularly their 5-HT(2)/D2 pKi ratio, was compatible with an atypical antipsychotic effect. Among these drugs, JL5 and JL13 showed a high degree of similarity with clozapine. Like clozapine, they did not induce catalepsy and stereotypy/hyperkinesia. Moreover, other motor effects were also reduced (ataxia, akinesia, dystony). and tremor and sialorrhea were completely absent with these two molecules.

Comparative study of typical neuroleptics, clozapine and newly synthesized clozapine-analogues: correlations between neurochemistry and behaviour.

Original bioisosteric analogues of clozapine were evaluated for potential disinhibitory and/or antidepressant effects using the open-field test in the rat and Porsolt's forced swimming test in the mouse. Attempts to relate the behavioural results to the binding affinities for dopamine (D1, D2), serotonin (5-HT(2)) and muscarinic (M) receptors were also undertaken. In the open-field test, two main profiles were observed. The first profile corresponded to disinhibitory molecules resembling diazepam and ritanserin. The second profile corresponded to antipsychotic compounds resembling either typical (haloperidol, clothiapine) or atypical (clozapine) neuroleptics. The results obtained in the forced swimming test confirmed the neuroleptic-like activity of the second group of compounds, while two compounds of the first group (JL 3 and JL 26) showed an antidepressant-like activity, JL 3 being as active as imipramine. While it was not possible to relate the first profile to any binding interaction, a relation could be established among the second group of compounds between the typical or atypical antipsychotic behavioural profile and the 5-HT(2)/D2 ratio.

New dibenzazepine derivatives with disinhibitory and/or antidepressant potential: neurochemical and behavioural study in the open-field and forced swimming tests.

J. Delarge

Papers

Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives.

In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators.

Recent advances in the chemistry of cholecystokinin receptor ligands (agonists and antagonists).

Comparative study of typical neuroleptics, clozapine and newly synthesized clozapine-analogues: correlations between neurochemistry and behaviour.

New dibenzazepine derivatives with disinhibitory and/or antidepressant potential: neurochemical and behavioural study in the open-field and forced swimming tests.