Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC = 6 ± 2 μM.

Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity Relationship Study.

Screening of a small compound library at the three excitatory amino acid transporter subtypes 1-3 (EAAT1-3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC 20 μM) compared to EAAT2 and EAAT3 (IC > 300 μM). This prompted us to subject 1a to an elaborate structure-activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold.

Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH-102.

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood-brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.

New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH-101 and UCPH-102.

In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways.

Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes.

The electron-donor and unique redox properties of the tetrathiafulvalene (TTF, 1) moiety have led to diverse applications in many areas of chemistry. Monopyrrolotetrathiafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes (BPTTFs, 5) are useful structural motifs and have found widespread use in fields such as supramolecular chemistry and molecular electronics. Protocols enabling the synthesis of functionalised MPTTFs and BPTTFs are therefore of broad interest.

Mechanistic evaluation of motion in redox-driven rotaxanes reveals longer linkers hasten forward escapes and hinder backward translations.

Mechanistic understanding of the translational movements in molecular switches is essential for designing machine-like prototypes capable of following set pathways of motion. To this end, we demonstrated that increasing the station-to-station distance will speed up the linear movements forward and slow down the movements backward in a homologous series of bistable rotaxanes. Four redox-active rotaxanes, which drove a cyclobis(paraquat-p-phenylene) (CBPQT(4+)) mobile ring between a tetrathiafulvalene (TTF) station and an oxyphenylene station, were synthesized with only variations to the lengths of the glycol linker connecting the two stations (n = 5, 8, 11, and 23 atoms).

Quantification of the π-π interactions that govern tertiary structure in donor-acceptor [2]pseudorotaxanes.

Flexibility in pseudorotaxanes and interlocked molecules that rely on interactions between π-donor-acceptor subunits provides access to folded structures reminiscent of the tertiary structure of proteins. While they have been described before, only now have we been able to quantify one such tertiary structure by making use of pseudorotaxanes designed for the purpose. Here, the enhanced stability of a pseudorotaxane inside a folded structure is measured to be ΔG = ca.

Molecular logic gates using surface-enhanced Raman-scattered light.

A voltage-activated molecular-plasmonics device was created to demonstrate molecular logic based on resonant surface-enhanced Raman scattering (SERS). SERS output was achieved by a combination of chromophore-plasmon coupling and surface adsorption at the interface between a solution and a gold nanodisc array. The chromophore was created by the self-assembly of a supramolecular complex with a redox-active guest molecule.

Turning on resonant SERRS using the chromophore-plasmon coupling created by host-guest complexation at a plasmonic nanoarray.

An active molecular plasmonics system is demonstrated where a supramolecular chromophore generated in a host-guest binding event couples with the localized surface plasmon resonance (LSPR) arising from gold nanodisc gratings. This coupling was achieved by wavelength-matching the chromophore and the LSPR with the laser excitation, thus giving rise to surface-enhanced resonance Raman scattering (SERRS). The chromophore is a broad charge-transfer (CT) band centered at 865 nm (epsilon = 3500 M(-1) cm(-1)) generated by the complexation of cyclobis(paraquat-p-phenylene) (CBPQT(4+)) and the guest molecule tetrathiafulvalene (TTF).

Determination of binding strengths of a host-guest complex using resonance Raman scattering.

The detection of analyte-binding events by receptors is drawing together the fields of Raman spectroscopy and supramolecular chemistry. This study is intended to facilitate this cohering by examining a model in the solution phase. The resonance Raman scattering (RRS) spectra of the complexation between tetrathiafulvalene (TTF) and cyclobis(paraquat-p-phenylene) (CBPQT(4+)) has been used as the model system to characterize the binding event of a host-guest system.

Two classes of alongside charge-transfer interactions defined in one [2]catenane.

A [2]catenane, which incorporates hydroquinone (HQ) and a sterically bulky tetrathiafulvalene (TTF) into a bismacrocycle, has been designed to probe the alongside charge-transfer (CT) interactions taking place between a TTF unit and one of the bipyridinium moieties in the tetracationic cyclophane cyclobis(paraquat-p-phenylene) (CBPQT4+). A template-directed strategy employs the HQ unit as the primary template for formation of the tetracationic cyclophane CBPQT4+, affording the desired [2]catenane structure but as an uncharacteristic green solid. The X-ray crystal structure and detailed 13C NMR assignments have identified a stereoselective preference for catenation about the cis isomer.

Functionally rigid bistable [2]rotaxanes.

Two-station [2]rotaxanes in the shape of a degenerate naphthalene (NP) shuttle and a nondegenerate monopyrrolotetrathiafulvalene (MPTTF)/NP redox-controllable switch have been synthesized and characterized in solution. Their dumbbell-shaped components are composed of polyether chains interrupted along their lengths by (i) two pi-electron-rich stations-two NP moieties or a MPTTF unit and a NP moiety-with (ii) a rigid arylethynyl or butadiynyl spacer situated between the two stations and terminated by (iii) flexibly tethered hydrophobic stoppers at each end of the dumbbells. This modification was investigated as a means to simplify both molecular structure and switching function previously observed in related bistable [2]rotaxanes with flexible spacers between their stations and incorporating a cyclobis(paraquat-p-phenylene) (CBPQT4+) ring.