GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines

Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo[7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 20 a , K_i=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 23 a , K_i=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ₁ and σ₂ receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands.     

Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([¹⁸F] 7b ) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([³H₂] 15b ), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1-GluN2A ligand-binding domain.     

[2.2]Paracyclophane-Derived Planar-Chiral Hydrogen-Bond Receptors

The development of planar-chiral hydrogen-bond donors based on the [2.2]paracyclophane scaffold is discussed. General strategies to access functionalized enantiopure [2.2]paracyclophane derivatives are briefly reviewed, with the focus on suitable precursors for the synthesis of planar-chiral thiourea derivatives. The synthesis of fourteen hydrogen-bond donors is described. The interaction of four thiourea derivatives with hydrogen-bond acceptors (DMSO and tetramethylammonium chloride) was investigated by ¹H NMR spectroscopy and X-ray crystallography. A selection of enantiomerically pure planar-chiral derivatives was applied in asymmetric hydrogen-bond catalysis.     

Aryl[2.2]paracyclophane-Based Chiral Regioisomeric Analogs of Salicyl Aldehyde: Novel Sources for Construction of Phenoxy-Imine Ligands

The efficient, high-yield approaches to two novel regioisomeric salicyl aldehyde analogs, 4-formyl-13-(2-hydroxyphenyl)-[2.2]paracyclophane and 4-formyl-12-(2-hydroxyphenyl)-[2.2]paracyclophane ( iso -FHPhPC and pseudo -FHPhPC , respectively), constructed on the basis of an aryl[2.2]paracyclophane backbone are described. The key stage of the backbone formation is the Suzuki cross-coupling of paracyclophanyl halides with arylboronic acids. Efficient procedures for the resolution of the racemic hydroxy aldehydes into enantiomers via Schiff bases with enantiomers of α-phenylethyl amine were elaborated, and the absolute configurations of enantiomers were established on the basis of X-ray analysis of diastereomeric imines. Starting from these chiral hydroxy aldehydes the first representatives of bi-, tri-, and tetradentate phenoxy-imine ligands belonging to an aryl[2.2]paracyclophane family were obtained. The induction power of the ligands was tested in the Et₂Zn asymmetric addition to aldehydes.     

Highly Stereoselective Synthesis of Novel Multistereogenic Bis‐Bifunctional Ligands Based on [2.2]Paracyclophane‐ 4,7‐quinone,their Structure Elucidation and Application in Asymmetric Catalysis

Bis‐bifunctional cis‐4,7‐diarylsubstituted‐4,7‐dihydroxy‐4,7‐dihydro[2.2]paracyclophanes 3–6 were synthesized by a highly diastereoselective reaction of ortho‐substituted aryllithium reagents with [2.2]paracyclophane‐4,7‐quinone ( 1 ). Enantiomerically pure diols 3–5 were tested as chiral inductors in the enantioselective addition of diethylzinc to benzaldehyde (up to 93.5% ee). Acid dehydration of cis‐4,7‐di(2‐methoxyphenyl)‐4,7‐dihydroxy‐4,7‐dihydro[2.2]paracyclophane ( 3 ) results in 4,7‐dihydro‐7,8‐di(2‐methoxyphenyl)[2.2]paracyclophane‐4‐one ( 8 ) – a planar chiral cyclohexadienone of the [2.2]paracyclophane series with a para‐semiquinoid substructure. X‐Ray investigations of compounds 3, 4 and 8 were performed.     

Functional Paracyclophanes: Synthesis of [2.2]Paracyclophanemethyldithiocarbonates Using Thione–Thiol Rearrangement of S,O-Dithiocarbonates (Benzyl Schönberg Rearrangement) at Mild Conditions

A pathway to benzylic [2.2]paracyclophane thiol derivatives was investigated using the benzyl Schönberg rearrangement.     

Phenyliodine Diacetate‐Mediated para‐Functionalizations of Amido‐ and Amino‐Substituted [2.2]Paracyclophanes

The reaction of N‐[2.2]paracyclophanyl‐substituted amides or amines with phenyliodine diacetate (PIDA) and protic nucleophiles affords mixed para‐substituted [2.2]paracyclophane derivatives in moderate to good yields. As protic nucleophiles carboxylic acids and alcohols as well as pyridine hydrobromide can be used. 4‐Hydroxy[2.2]paracyclophane reacts in an analogous manner.

     

Palladium‐Catalyzed C?H Bond Acetoxylation: An Approach to ortho‐Substituted Hydroxy[2.2]paracyclophane Derivatives

The palladium‐catalyzed direct C H bond acetoxylation of [2.2]paracyclophanes has been investigated. Various mono‐ and disubstituted [2.2]paracyclophanes were subjected to typical Sanford acetoxylation conditions. Oxime ethers, an oxime acetate, a pyridine, and a pyrazole with [2.2]paracyclophane cores underwent direct ortho‐acetoxylation in good to excellent yields using 1–5 mol% of palladium(II) acetate in combination with iodobenzene diacetate as oxidant. The reactions could be performed on a multigram scale, and the ortho‐acetoxylated [2.2]paracyclophanes were suitable for further functionalizations affording a hydroxy[2.2]paracyclophane derivative and a planar chiral benzoxazole.     

Through-space conjugated polymer containing [2.2]paracyclophane and dithiafulvene units in the main chain

A new through-space conjugated polymer containing alternate [2.2]paracyclophane and dithiafulvene units was synthesized by cycloaddition polymerization of aldothioketene derived from 4,16-diethynyl[2.2]paracyclophane. The obtained polymer was soluble in common organic solvents and could form thin films. UV–vis absorption spectrum of the polymer revealed that its conjugation length increased due to the through-space interaction of the [2.2]paracyclophane units. The polymer formed a charge transfer (CT) complex with 7,7,8,8-tetracyanoquinodimethane (TCNQ) in DMSO.     

Synthesis, Structure, and Properties of Aromatic Ring-Layered Polymers Containing Ferrocene as a Terminal Unit

[2.2]Paracyclophane-layered polymers 4a and 4b end-capped by ferrocene and [2.2]paracyclophane, respectively, were synthesized by using a xanthene skeleton as a scaffold. Two model compounds, 4,5-bis(ferrocenylethynyl)-9,9-dimethylxanthene 7 and pseudo-p-bis(4-ferrocenylethynyl-9,9-dimethylxanthen-5-yl)[2.2]paracyclophane 8, comprising ferrocenes arranged in a face-to-face manner were also prepared. According to the X-ray molecular structure of compound 8, [2.2]paracyclophane between the ferrocenes had sufficient space for twisting and there was no interaction between two ferrocenes via [2.2]paracyclophane in the ground state. These polymers exhibited blue-light emission originating from the layered cyclophanes; however, the photoluminescence intensity of polymer 4a was lower than that of polymer 4b. The fluorescence emission of polymer 4a was effectively quenched by the end-capping ferrocene group. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

[2.2]Paracyclophane as a Target of the Organic Solid State: Emergent Properties via Supramolecular Construction

In this account, we review the synthesis of [2.2]paracyclophanes in the organic solid state. Reactions in crystalline solids provide a means to obtain molecules with high degrees of stereocontrol that can also be unattainable in solution. We show that [2.2]paracyclophanes form in the solid state stereospecifically and in quantitative yield via intermolecular [2+2] double photodimerization reactions. The double cycloaddition that affords a paracyclophane in the solid state does not readily occur in solution. Small molecules in the form of hydrogen-bond-donor templates can provide access to [2.2]paracyclophanes in a solid by design. A [2.2]paracyclophane obtained using a hydrogen-bond template is shown to exhibit attractive optical properties and has been employed as a building block of a metal-organic framework (MOF).     

Organic Small Molecules for Photonics and Electronics from the [2.2]Paracyclophane Scaffold

In the search for molecules for organic photonics and electronics, several strategies have been used to modulate physical and chemical properties of [2.2]paracyclophane derivatives by sequential functionalization of their three-dimensional cores. This review summarizes the major design and synthetic strategies for tuning paracyclophane-containing small molecules by introducing various moieties featuring (hetero)aromatic rings directly connected to each other, as well as alternating (hetero)aryl and ethylene or ethynylene units. Several examples are presented that elucidate the structural, optical, and electronic consequences of incorporating these fragments in the aromatic decks, particularly relating to applications in organic optoelectronics.     

Mapping the Melatonin Receptor. 8. Selective MT2 Agonists Derived from 5,6-Dihydroindolo[2,1-a]isoquinolines and Related Systems

A series of substituted indolo[2,1-a]isoquinolines and indolo[1,2-a]benzoxazines have been prepared, as melatonin analogues, to investigate the nature of the binding site of the melatonin receptor. Agonist and antagonist potency of all the analogues was measured using the [35S]GTPγS binding assay protocol. The binding affinity of the analogues were measured by competition binding studies against the human MT1 (hMT1) and MT2 (hMT2) receptors stably transfected in Chinese Hamster Ovarian (CHO) cells, using 2-[¹²⁵I]-iodomelatonin, as a ligand. N-Acetyl 2-(10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolin-12-yl)propyl-1-amine (12 a) binds strongly to both the hMT1 and hMT2 receptors, and shows a preference for the hMT2, as does its propanamido counterpart 12 b . The introduction of two methyl groups into their side chain, analogues 15 a and 1 5 b , leads to antagonism, in the case of the former, and drastically diminishes its hMT1 binding; an analogous profile is seen for 15 b , which, however, is a partial agonist. Introduction of chlorine or methoxy groups into ring 4 gives compounds, that are weakly binding, with a preference for MT2. Substitution of oxygen for carbon at position 5 gives the indolo[1,2-c]benzoxazines 33 , 36 a and b , that bind strongly to the human receptors, 33 , 36 b being potent agonists at the melatonin receptors, but do not discriminate between hMT1 and hMT2.     

Synthesis and in Vitro Characterisation of Ifenprodil‐Based Fluorescein Conjugates as GluN1/GluN2B N‐Methyl‐D‐aspartate Receptor Antagonists

GluN2B‐containing NMDA receptors are involved in many important physiological functions and play a pivotal role in mediating pain as well as in several neurodegenerative disorders. We aimed to develop fluorescent probes to target the GluN2B subunit selectively in order to allow better understanding of the relationships between receptor localisation and physiological importance. Ifenprodil, known as the GluNR2B antagonist of reference, was chosen as the template for the elaboration of probes. We had previously reported a fluorescein conjugate that was shown (by confocal microscopy imaging of DS‐red‐labelled cortical neurons) to bind specifically to GluN2B. To elaborate this probe, we explored the influence of both the nature and the attachment point of the spacer between the fluorophore and the parent compound, ifenprodil. We performed chemical modifications of ifenprodil at the benzylic position and on the phenol ring by introducing secondary amine or amide functions and evaluated alkyl chains from two to 20 bonds either including or not including secondary amide functions as spacers. The previously developed probe was found to display the greatest activity in the inhibition of NMDA‐induced Ca²⁺ influx by calcium imaging experiments on HEK293 cells transfected with the cDNA encoding for GluN1‐1A and GluN2B. Further investigations revealed that this probe had a neuroprotective effect equivalent to that of ifenprodil in a standard test for neurotoxicity. Despite effects of lesser amplitude with these probes relative to ifenprodil, we demonstrated that they displaced [³H]ifenprodil in mouse brain slices in a similar manner.     

Synthesis of Planar Chiral Carbazole Derivatives Bearing a [2.2]Paracyclophane Skeleton

The synthesis of planar chiral carbazoles bearing a [2.2]paracyclophane backbone is described. Starting from readily available 4-bromo[2.2]paracyclophane planar chiral carbazoles are obtained in a two-step synthesis by Pd-catalyzed C N cross-coupling and subsequent oxidative cyclization.     

Efficient Modular Synthesis of Isomeric Mono‐ and Bispyridyl[2.2]paracyclophanes by Palladium‐Catalyzed Cross‐ Coupling Reactions

Pyridyl‐substituted [2.2]paracyclophanes build a multifunctional structural motif that is useful in material chemistry, catalysis and for luminescent structures. Nonetheless, there is still a lack of general methods for the synthesis of these structures tolerating easily accessible bromides as well as different isomeric pyridyl groups. Hence the coupling of functionalized [2.2]paracyclophanes with various substituted and functionalized pyridyl derivatives was achieved using Stille, Suzuki and Kumada coupling conditions. Hereby the Stille coupling of a [2.2]paracyclophane is presented as a versatile reaction for the formation of heteromeric [2.2]paracyclophane‐containing biaryl structures.

     

Early and Delayed Impact of Nanosilver on the Glutamatergic NMDA Receptor Complex in Immature Rat Brain

Silver nanoparticles (AgNPs) are the one of the most extensively used nanomaterials. The strong antimicrobial properties of AgNPs have led to their use in a wide range of medical and consumer products. Although the neurotoxicity of AgNPs has been confirmed, the molecular mechanisms have not been extensively studied, particularly in immature organisms. Based on information gained from previous in vitro studies, in the present work, we examine whether ionotropic NMDA glutamate receptors contribute to AgNP-induced neurotoxicity in an animal model of exposure. In brains of immature rats subjected to a low dose of AgNPs, we identified ultrastructural and molecular alterations in the postsynaptic region of synapses where NMDA receptors are localized as a multiprotein complex. We revealed decreased expression of several NMDA receptor complex-related proteins, such as GluN1 and GluN2B subunits, scaffolding proteins PSD95 and SynGAP, as well as neuronal nitric oxide synthase (nNOS). Elucidating the changes in NMDA receptor-mediated molecular mechanisms induced by AgNPs, we also identified downregulation of the GluN2B-PSD95-nNOS-cGMP signaling pathway which maintains LTP/LTD processes underlying learning and memory formation during development. This observation is accompanied by decreased density of NMDA receptors, as assessed by a radioligand binding assay. The observed effects are reversible over the post-exposure time. This investigation reveals that NMDA receptors in immature rats are a target of AgNPs, thereby indicating the potential health hazard for children and infants resulting from the extensive use of products containing AgNPs.     

Tricycloundecane Derivatives as Potential N‐Methyl‐D‐aspartate (NMDA) Receptor and Voltage‐Gated Calcium Channel Modulators

Neurodegenerative disorders are debilitating conditions characterised by progressive dysfunction and death of neuronal cells. Amidst the proposed mechanisms of neurodegeneration, the effects of excitotoxicity via N‐methyl‐D ‐aspartate (NMDA) receptor stimulation and activation of voltage‐gated calcium channels (VGCC) on neuronal cells are prominent. This has led to the development of polycyclic cage molecules such as NGP1‐01, which exhibit neuroprotective properties through NMDA receptor and VGCC modulation. The medicinal potential of structurally related tricycloundecanes that are open‐cage or rearranged polycyclic moieties has not been explored. This study is therefore focused on the synthesis of a series of novel tricycloundecane derivatives and their ability to inhibit NMDA receptors and VGCC. Significant NMDA receptor inhibition was observed for tricyclo[6.2.1.0^2,7]undec‐9‐ene‐3,6‐dione ( 4 , 78 %) and 6‐hydroxytricyclo[6.2.1.0^2,7]undec‐9‐en‐3‐one ( 5 , >95 %) at a concentration of 100 μM . The highest inhibitory activity was observed for 6‐(benzylimino)tricyclo[6.2.1.0^2,7]undec‐9‐en‐3‐one ( 9 , >95 %), which is in the same range as the inhibitory activity of MK‐801 (dizocilpine). In the VGCC inhibition assay, 6‐(benzylamino)tricyclo[6.2.1.0^2,7]undeca‐4,9‐dien‐3‐one ( 8 , 34 %), 9 (38 %) and 2‐(benzylamino)‐3,6‐epoxytricyclo[6.2.1.0^5,10]undecan‐9‐ol ( 12 , 40 %) showed statistically significant (p<0.05) VGCC inhibition.     

Cyclophane-containing polymers

In spite of the remarkable progress of cyclophane chemistry, syntheses of polymers containing cyclophane units in the main chain and side chain by utilizing the transannular π–π interaction are considerably limited. In this review, syntheses, properties, and applications of [m,n]cyclophanes-containing (m?3 and n?3) polymers prepared to date are presented. The main body of the review is classified into broadly four categories: introduction of (i) main-chain-type cyclophane-containing polymers, (ii) side-chain-type cyclophane-containing polymers, (iii) rigid-rod conjugated polymers containing pendent aromatic rings, and finally (iv) aromatic-ring-layered polymers comprising [2.2]paracyclophane.     

Efficient and Scalable Kinetic Resolution of Racemic 4‐Formyl[2.2]paracyclophane via Asymmetric Transfer Hydrogenation

Herein we wish to report a new non‐enzymatic kinetic resolution of racemic 4‐formyl[2.2]paracyclophane based on Noyori asymmetric transfer hydrogenations (KR‐ATH). Our approach, which provides an efficient access to enantiopure (R_p)‐ and (S_p)‐4‐formyl[2.2]paracyclophane (>99% ee, 39% and 41% isolated yields, respectively), is operationally simple and can be run on the gram‐scale thus confirming the practical applicability of this method.