Robert Petroski

Eliasof, S., McIlvain, HB, Petroski, RE, Foster, AC and Dunlop, J.(2001), Pharmacological characterization of threo-3-methylglutamic acid with excitatory amino acid transporters in native and recombinant systems. Journal of Neurochemistry, 77: 550–557. doi: 10.1046/j. ...

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

The putative neurotrophic effects of basic fibroblast growth factor (bFGF) were tested on embryonic hypothalamic neurons in dissociated cell culture. Basic FGF dramatically increased the survival of embryonic hypothalamic astrocytes plated on a poly-L-lysine (PLL) substrate. Basic FGF treatment also increased the number of hypothalamic neurons surviving in vitro; however, no neurotrophic effects were observed when astrocyte proliferation was prevented by using serum-free N2 medium or by using the mitotic inhibitor cytosine arabinoside. In contrast to effects when PLL was used as a substrate, bFGF reduced the survival of hypothalamic neurons plated on a confluent, contact-inhibited monolayer of astrocytes. This effect appears to be due to the direct actions of bFGF on astrocytes: treatment of confluent astrocytes with 5 ng/ml bFGF caused the protoplasmic astrocytes to develop a fibrillar morphology and reduced the ability of the astrocyte monolayer to promote neuronal survival after a further 24 hr in bFGF-free medium. It is concluded that in addition to its mitogenic effects, bFGF acts as a differentiation factor for protoplasmic astrocytes in vitro, and these morphological and functional changes may reflect the process of normal astrocytic development and response to brain injury in vivo.

4-Acetylamino-2-(3, 5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A K i 2.3 nM, ...

In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA 2A ) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of ...

Glutamate is the major excitatory neurotransmitter in the central nervous system and is tightly regulated by cell surface transporters to avoid increases in concentration and associated neurotoxicity. Selective blockers of glutamate transporter subtypes are sparse and so knock-out animals and antisense techniques have been used to study their specific roles. Here we used WAY-855, a GLT-1-preferring blocker, to assess the role of GLT-1 in rat hippocampus. GLT-1 was the most abundant transporter in the hippocampus at the mRNA level. According to [(3)H]-l-glutamate uptake data, GLT-1 was responsible for approximately 80% of the GLAST-, GLT-1-, and EAAC1-mediated uptake that occurs within dissociated hippocampal tissue, yet when this transporter was preferentially blocked for 120 h with WAY-855 (100 microm), no significant neurotoxicity was observed in hippocampal slices. This is in stark contrast to results obtained with TBOA, a broad-spectrum transport blocker, which, at concentrations that caused a similar inhibition of glutamate uptake (10 and 30 microm), caused substantial neuronal death when exposed to the slices for 24 h or longer. Likewise, WAY-855, did not significantly exacerbate neurotoxicity associated with simulated ischemia, whereas TBOA did. Finally, intrahippocampal microinjection of WAY-855 (200 and 300 nmol) in vivo resulted in marginal damage compared with TBOA (20 and 200 nmol), which killed the majority of both CA1-4 pyramidal cells and dentate gyrus granule cells. These results indicate that selective inhibition of GLT-1 is insufficient to provoke glutamate build-up, leading to NMDA receptor-mediated neurotoxic effects, and suggest a prominent role of GLAST and/or EAAC1 in extracellular glutamate maintenance.

Note to users: The section "Articles in Press" contains peer reviewed accepted articles to be published in this journal. When the final article is assigned to an issue of the journal, the "Article in Press" version will be removed from this section and will appear in the associated ...

SAR of lead benzothiophene H 1 -antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H 1 -antihistamines with a range of projected half-lives in humans were identified. ...

Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABA A receptors from rat brain and acts as a positive allosteric modulator of GABA A receptor ...

Clinically used benzodiazepine and nonbenzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter GABA at the GABA A receptor ...

A method for selectively labeling cultured neurons using the vital dye, 5(6)-carboxyfluorescein diacetate (CFDA), is described. This non-fluorescent membrane-permeant dye is cleaved by cytosolic esterases into the fluorescent anion, 5(6)-carboxyfluorescein (CF). Both astrocytes and neurons exhibit brilliant fluorochromasia within minutes of CFDA loading. However, following a brief rinse in buffered saline in the absence of CFDA, the astrocytes rapidly lose their cellular fluorescence while the neurons retain the dye for several hours. The fluorochromasia is uniformly distributed throughout the soma and processes which greatly facilitates the morphological identification of viable neurons. In addition, this protocol can be used to conveniently quantify neuronal survival in assays of the activities of neurotrophic or neurotoxic substances.

A series of indene analogs of the H1-antihistamine (−)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led ...

Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had ...