The benzodiazepine recognition site of the mammalian brain GABAA receptor (responsible for the majority of neuronal inhibition in the mammalian CNS) has taken its name from the chemical structures that we now know to interact specifically with this allosteric site. These benzodiazepines were introduced into clinical practice in the 1960s and proved to be enormously successful in the treatment of anxiety and sleep disorders. The pharmacological spectrum of activity for benzodiazepine site ligands is much wider. While it was recognised early that benzodiazepines were efficacious anticonvulsants and muscle relaxants, advances in our understanding of their mechanisms of action over the intervening years have revealed even greater potential for their clinical use. Early attempts to decrease the sedative potential of the benzodiazepine ligands, without losing their anxiolytic activity, proved frustratingly difficult. Meanwhile, the exciting potential of partial inverse agonists at this site to improve performance in certain cognitive tasks appeared to be confounded by their proconvulsant activity. This review briefly summarises some of the progress that has been made, and attempts to put the potential for further exploitation of this allosteric site into perspective. This review summarises the patents filed in the three year period to June 1999.
The mixed CCK antagonist N-(3-oxo- 2,3-dihydro-1H-pyrazol-4-yl)-indole-carboxamide MPP with a binding affinity of 25nM /20nM and the CCK1 selective 3-oxo-1,2-diphenyl-2,3-dihydro-1Hpyrazol- 4-yl)-N'-phenyl-urea MPM (IC50 = 25nM) represent the best two compounds of an amide and a urea pyrazoline series, which were previously evaluated in mice (Part 1) for their CNS activity. The long term in vivo and in vitro evaluation is described in this part. Stress was induced for a 4 week period daily. A dose of 0.5 mg/kg of MPP and MPM showed a significant antidepressant effect in the foced swim test in rats, which was in enhanced within a 4 week test period. The mixed CCK antagonist MPM only occurred anxiolytic properties in the elevated X-maze in rats at a 0.5 mg/kg dose. For the stress induced rats, the MPP and MPM treatment reversed the effects of stress on the dendritic atrophy in hippocampal CA3 pyramidal neurons. A reduction of organ weight was reversed for the adrenal gland, when the animals were treated with the CCK antagonists MPP and MPM over a period of 4 weeks.
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Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimida-zolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 microg/ml against the multiresistant Staphylococcus aureus (MRSA).
The preparation of an extremely cheap and novel resin synthesised from a commercially available ion exchange resin is described.The free carboxylic acid group of the resin was converted into a methylester.Subsequent reduction of this ester to the corresponding alcohol has been carried out in one step, by using a solution of DIBAH as a reducing agent.The application of this resin for solid phase combinatorial synthesis has been evaluated by synthesizing 2 representative peptides and 2 selected 1,4-benzodiazepines.
3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK1 receptor selectivity to CCK2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties.
Asperlicin was the first non-peptidal lead structure from nature 12 and analogues thereof were studied as CCK ligands. 13Simplification of this lead structure by Merck led to Devazepide, 14 a potent CCK 1 selective cholecystokinin antagonist (Figure 1), containing a 1,4-benzodiazepine template and an indole moiety.Proglumide 15 was the first glutamic acid based agent, marketed as Milid for the treatment of ulcer.Lorglumide, a derivative of proglumide, 16 (Figure 1) is one of several CCK receptor antagonists 17 and served as experimental standard.The indolyl amide of devazepide was replaced by a urea linkage and Merck's L-365,260 resulted in a CCK 2 selective antagonist. 18Z-360 is a CCK 2 -gastrin receptor antagonist and progressed into phase 2 trial with pancreatic cancer. 19Z-360 is the most recent derivative derived from this original lead structure, with improved selectivity and bioavailability.All structural optimisations did only partly address the main underlying problem with respect to poor pharmacokinetic properties, such as a low water solubility and very low membrane penetration, as a result of a large polar surface area of the molecules and a relatively high molecular weight.
Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolarin vitroactivity and anticancer activityin vivofor colon and pancreatic cancer.
The aim of this study was firstly to identify active molecules in herbs, that are traditionally used for the treatment of snake bite, such as Curcuma antinaia, Curcuma contravenenum, Andrographis paniculata, and Tanacetum parthenium; secondly to test similar structurally related molecules and finally to prepare and evaluate an efficient formulation against Ophiophagus hannah venom intoxification.Three labdane based compounds, including labdane dialdehyde, labdane lactone, and labdane trialdehyde and two lactones including 14-deoxy-11,12-didehydroandrographolide and parthenolide were isolated by column chromatography and characterised.Using the isolated rat phrenic nerve-hemidiaphragm preparation, the antagonistic effect of crude extracts, isolated compounds and prepared formulations were measured in vitro on the inhibition of the neuromuscular transmission.Inhibition on muscle contraction, produced by the 5 μg/mL venom, was reversed by test agents in organ bath preparations.A labdane trialdehyde, isolated from C. contravenenum, was identified as the best antagonising agent in the low micromolar range.Tests on formulations of the most potent C. contravenenum extract showed, that the suppository with witepsol H15 was an effective medicine against O. hannah venom.This study elucidated the active compounds, accounting for the antivenin activity of traditionally used herbs and suggested the most suitable formulation, which may help to develop potent medicines for the treatment of snake bite in the future.
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