The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.
Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field.Keywords: Glutamate receptors, kainic acid receptors, competitive antagonists, medicinal chemistry, structureactivity relationship studies T he common R-amino acid (S)-glutamate (Glu) functions as the major endogenous excitatory neurotransmitter in the central nervous system (CNS). Upon its release into the synaptic cleft, it activates the Glu receptors. These receptors have been divided into two major classes: the ligand-gated ion channels named the ionotropic receptors (iGluRs) and the slower acting G-protein coupled receptors named the metabotropic receptors (mGluRs). On the basis of ligand affinity studies, the class of iGluRs has been divided into three subgroups: the N-methyl-D-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and kainate (KA) receptors (1-3). With focus on the KA receptors, it is believed that this subgroup of receptors are potential therapeutic targets in diseases such as schizophrenia, major depression, pain, and epilepsy. In order to elucidate the role of the KA receptors, medicinal chemists have attempted to develop subtype-selective KA receptor ligands for the last two to three decades. Although extensive effort has been made, only a limited number of subtype-selective KA receptor ligands have been reported. For a comprehensive review on KA receptor agonists, see our recent review (4). The aim of this review is to provide the medicinal chemists (and others) who have an interest in the structure-activity relationship (SAR) of competitive KAR antagonists with an overview of the field. This information may aid the design of new subunit-selective KA receptor antagonists.
Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 μM.
The lack of commercially available primary murine endothelial cells prompted us to isolate and cultivate this cell type. We report here the effect of sex steroids on the in vitro growth of murine aortic endothelial cells. Murine aortic endothelial cells were isolated by a combination of explant outgrowth from aortic rings and enzymatic digestion. The endothelial nature of the cells was verified by uptake of acylated low-density lipoprotein and positive staining for CD-31. Murine aortic endothelial cell growth is stimulated by physiological concentrations of estrogen. Progesterone, when given simultaneously with estrogen, inhibited the stimulatory growth effect of estrogen. Murine aortic endothelial cells grown in vitro continue to express messenger ribonucleic acid for proteins related to endothelial growth. These include vascular endothelial growth factor, its receptors Flt-1 and Flk-1, and the angiogenesis-associated transcription factor, Ets-1.
The lack of commercially available primary murine endothelial cells prompted us to isolate and cultivate this cell type. We report here the effect of sex steroids on the in vitro growth of murine aortic endothelial cells. Murine aortic endothelial cells were isolated by a combination of explant outgrowth from aortic rings and enzymatic digestion. The endothelial nature of the cells was verified by uptake of acylated low-density lipoprotein and positive staining for CD-31. Murine aortic endothelial cell growth is stimulated by physiological concentrations of estrogen. Progesterone, when given simultaneously with estrogen, inhibited the stimulatory growth effect of estrogen. Murine aortic endothelial cells grown in vitro continue to express messenger ribonucleic acid for proteins related to endothelial growth. These include vascular endothelial growth factor, its receptors Flt-1 and Flk-1, and the angiogenesis-associated transcription factor, Ets-1.
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