Discovery of diaminobutane derivatives as Ca(2+)-permeable AMPA receptor antagonists

We designed and synthesized a series of the polyamine derivatives as potent Ca(2+)-permeable AMPA receptor antagonists. In the course of this study, we found that the polyamine derivatives exhibited strong hypotensive activity which was undesirable activity for neuroprotective agents. Therefore, we tried to find non-hypotensive antagonists by structural modification of such compounds. Through this derivatization, we obtained the diamine compounds having desired profiles. Especially, compound 8f, which was non-hypotensive and potent Ca(2+)-permeable AMPA receptor antagonist, showed neuroprotective effects in transient global ischemia models in gerbils.     

Synthesis of polyamine derivatives having non-hypotensive Ca2 +-permeable AMPA receptor antagonist activity

In order to obtain non-hypotensive and Ca2+-permeable AMPA receptor antagonists, we have synthesized a series of 1,4-bis(4-piperidinylmethyl)diaminobutanes. Compounds 13b, c, f had desirable properties.     

Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists

Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors.     

Evidence for Ca(2+)-permeable AMPA receptors in the olfactory bulb

-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs), a subtype of glutamate receptor, contribute to olfactory processing in the olfactory bulb (OB). These ion channels consist of various combinations of the subunits GluR1–GluR4, which bestow certain properties. For example, AMPARs that lack GluR2 are highly permeable to Ca²⁺ and generate inwardly rectifying currents. Because increased intracellular Ca²⁺ could trigger a host of Ca²⁺-dependent odor-encoding processes, we used whole cell recording as well as histological and immunocytochemical (ICC) techniques to investigate whether AMPARs on rat OB neurons flux Ca²⁺. Application of 1-naphthylacetyl spermine (NAS), a selective antagonist of Ca²⁺-permeable AMPARs (CP-AMPARs), inhibited AMPAR-mediated currents in subsets of interneurons and principal cells in cultures and slices. The addition of spermine to the electrode yielded inwardly rectifying current-voltage plots in some cells. In OB slices, olfactory nerve stimulation elicited excitatory responses in juxtaglomerular and mitral cells. Bath application of NAS with D,L-2-amino-5-phosphonovaleric acid (AP5) to isolate AMPARs suppressed the amplitudes of these synaptic responses compared with responses obtained using AP5 alone. Co²⁺ staining, which involves the kainate-stimulated influx of Co²⁺ through CP-AMPARs, produced diverse patterns of labeling in cultures and slices as did ICC techniques used with a GluR2-selective antibody. These results suggest that subsets of OB neurons express CP-AMPARs, including functional CP-AMPARs at synapses. Ca²⁺ entry into cells via these receptors could influence odor encoding by modulating K⁺ channels, N-methyl-D-aspartate receptors, and Ca²⁺-binding proteins, or it could facilitate synaptic vesicle fusion. GluR2; polyamines; cobalt; glutamate receptor; olfaction     

Synthesis and SAR of 5-aryl-furan-2-carboxamide derivatives as potent urotensin-II receptor antagonists

The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC₅₀ value of 6?nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.     

New indole amide derivatives as potent CRTH2 receptor antagonists

A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.     

Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells

Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca(2+)-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca(2+)-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.     

Conformationally restricted indolopiperidine derivatives as potent CCR2B receptor antagonists

The preparation and biological evaluation of a series of indolopiperidine CCR2B receptor antagonists possessing a conformationally restricted C-5 linker chain in combination with a restricted piperidine ring are described. Compared to the parent compound 1, analogue 8 shows a dramatic improvement in selectivity against a range of 5-HT and dopaminergic receptors.     

Early activation of Ca(2+)-permeable AMPA receptors reduces neurite outgrowth in embryonic chick retinal neurons.

Calcium entry through Ca(2+)-permeable AMPA/kainate receptors may activate signaling cascades controlling neuronal development. Using the fluorescent Ca(2+)-indicator Calcium Green 1-AM we showed that the application of kainate or AMPA produced an increase of intracellular [Ca(2+)] in embryonic chick retina from day 6 (E6) onwards. This Ca(2+) increase is due to entry through AMPA-preferring receptors, because it was blocked by the AMPA receptor antagonist GYKI 52466 but not by the N-methyl-D-aspartic acid (NMDA) receptor antagonist AP5, the voltage-gated Ca(2+) channel blockers diltiazem or nifedipine, or by the substitution of Na+ for choline in the extracellular solution to prevent the depolarizing action of kainate and AMPA. In dissociated E8 retinal cultures, application of glutamate, kainate, or AMPA reduced the number of neurites arising from these cells. The effect of kainate was prevented by the AMPA/kainate receptor antagonist CNQX and by GYKI 52466 but not by AP5, indicating that the reduction in neurite outgrowth resulted from the activation of AMPA receptors. Blocking Ca(2+) influx through L-type voltage-gated Ca(2+) channels with diltiazem and nifedipine prevented the effect of 10-100 microM kainate but not that of 500 microM kainate. In addition, joro spider toxin-3, a blocker of Ca(2+)-conducting AMPA receptors, prevented the effect of all doses of kainate. Neither GABA, which is depolarizing at this age in the retina, nor the activation of metabotropic glutamate receptors with tACPD mimicked the effects of AMPA receptor activation. Calcium entry via AMPA receptor channels themselves may therefore be important in the regulation of neurite outgrowth in developing chick retinal cells.     

Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR

Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM).     

Benzotriazinone and benzopyrimidinone derivatives as potent positive allosteric AMPA receptor modulators

AMPA receptors (AMPARs) have been demonstrated to be an important therapeutic CNS target. A series of substituted benzotriazinone and benzopyrimidinone derivatives were prepared with the aim to improve in vivo activity over the previously reported bis-benzoxazinone based AMPAKINE series from our laboratory. These compounds were shown to be potent, positive allosteric AMPAR modulators that have better in vivo activity and improved metabolic stability over the analogous benzoxazinone derivatives.     

2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as potent androgen receptor antagonists

The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).     

Azaindoles as potent CRTH2 receptor antagonists

A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed.     

Novel substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 receptor antagonists

Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.     

ATP-activated Ca(2+)-permeable channels in rat peritoneal macrophages.

The patch-clamp technique was used to study mechanisms of ATP-induced Ca2+ influx in rat peritoneal macrophages. The experiments on whole-cell and patch membranes have shown that extracellular ATP activates channels permeable to di- and monovalent inorganic cations. Ratios of unitary channel conductances in 105 mM Ca2+, Sr2+, Mn2+, Ba2+ and normal sodium solutions were 1.0, 0.95, 0.75, 0.55 and 0.85, respectively. The channels could open in the presence of non-hydrolyzable GTP analogues in artificial intracellular solution. The data are consistent with the hypothesis that a GTP-binding protein is involved in receptor-to-channel coupling.     

Quinazolindione derivatives as potent 5-HT3A receptor antagonists

5-HT_3A receptor antagonists have been used mainly for the treatment of nausea and vomiting. These days, the antagonists are of special interest due to their therapeutic potential to treat other diseases such as depression, psychotic disorder, drug abuse, and irritable bowel syndrome. To discover novel 5-HT_3A receptor antagonists, we screened our in-house small molecule library, resulting in identifying the quinazolindione derivatives as potent 5-HT_3A receptor antagonists. For the purpose of structure–activity relationship study, 24 quinazolindione analogues were biologically evaluated against 5-HT_3A receptor. Among those, KKHT10612 shows the best antagonistic effect against 5-HT_3A receptor with an IC₅₀ value of 0.8 μM which is comparable with that of the reference compound, MDL72222, and selectivity over T-type calcium channel as well.     

Synthesis and pharmacological evaluation of aryl aminosulfonamide derivatives as potent 5-HT6 receptor antagonists

A series of novel aryl aminosulfonamides was designed and synthesized as 5-HT₆ receptor ligands. Many compounds screened in a functional reporter gene based assay displayed potent antagonistic activity with Kb values in the range of 0.02–10 nM. The lead compound 11m exemplified in this series showed good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. The compound was selected for detailed profiling.     

Synthesis and evaluation of spirobenzazepines as potent vasopressin receptor antagonists

A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists.