RESUMO
Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.
RESUMO
Tetradentate diamino bis(thiolate) ligands (l-N2S2(2-)) with saturated linkages between heteroatoms support fully reduced [(Cu(l-N2S2))2Cu2] complexes that bear relevance as an entry point toward molecules featuring the Cu2ICu2II(µ4-S) core composition of nitrous oxide reductase (N2OR). Tetracopper [(Cu(l-N2(SMe2)2))2Cu2] (l-N2(SMe2H)2 = N1,N2-bis(2-methyl-2-mercaptopropane)-N1,N2-dimethylethane-1,2-diamine) does not support clean S atom oxidative addition but undergoes Cl atom transfer from PhICl2 or Ph3CCl to afford [(Cu(l-N2(SMe2)2))3(CuCl)5], 14. When introduced to Cu(I) sources, the l-N2(SArH)2 ligand (l-N2(SArH)2 = N1,N2-bis(2-mercaptophenyl)-N1,N2-dimethylethane-1,2-diamine), made by a newly devised route from N1,N2-bis(2-fluorophenyl)-N1,N2-dimethylethane-1,2-diamine, ultimately yields the mixed-valent pentacopper [(Cu(l-N2SAr2))3Cu2] (19), which has 3-fold rotational symmetry (D3) around a Cu2 axis. The single CuII ion of 19 is ensconced within an equatorial l-N2(SAr)2(2-) ligand, as shown by 14N coupling in its EPR spectrum. Formation of 19 proceeds from an initial, fully reduced product, [(Cu(l-N2SAr2))3Cu2(Cu(MeCN))] (17), which is C2 symmetric and exceedingly air-sensitive. While unreactive toward chalcogen donors, 19 supports reversible reduction to the all-cuprous state; generation of [19]1- and treatment with S atom donors only return 19 because structural adjustments necessary for oxidative addition are noncompetitive with outer-sphere electron transfer. Oxidation of 19 is marked by intense darkening, consistent with greater mixed valency, and by dimerization in the crystalline state to a decacopper species ([20]2+) of S4 symmetry.
RESUMO
Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.
Assuntos
Acetatos/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Glicoproteínas de Membrana/genética , Microglia/efeitos dos fármacos , Fenóis/farmacologia , Receptores Imunológicos/genética , Receptores X de Retinoides/genética , Hormônios Tireóideos/farmacologia , Acetatos/síntese química , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/patologia , Modelos Moleculares , Fenóis/síntese química , Fenoxiacetatos/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/imunologia , Elementos de Resposta , Receptores X de Retinoides/química , Receptores X de Retinoides/metabolismo , Transdução de SinaisRESUMO
Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.
RESUMO
The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptor modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy that directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.
Assuntos
Encéfalo/metabolismo , Terapia de Alvo Molecular , Pró-Fármacos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Amidas/química , Amidas/metabolismo , Amidas/farmacologia , Amidoidrolases/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Difusão , Camundongos , Camundongos Endogâmicos C57BL , Pró-Fármacos/farmacocinética , Distribuição TecidualRESUMO
Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.
Assuntos
Acetatos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Fenóis/farmacologia , Hormônios Tireóideos/agonistas , Substância Branca/efeitos dos fármacos , Acetatos/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Gliotoxina/toxicidade , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/etiologia , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Fenóis/uso terapêutico , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Remielinização/efeitos dos fármacos , Remielinização/genética , Hormônios Tireóideos/administração & dosagem , Fatores de Transcrição/genética , Substância Branca/citologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.
RESUMO
Thyroid hormone is a principal regulator of essential processes in vertebrate physiology and homeostasis. Synthetic derivatives of thyroid hormone, known as thyromimetics, display desirable therapeutic properties. Thoroughly understanding how thyromimetics distribute throughout the body is crucial for their development and this requires appropriate bioanalytical techniques to quantify drug levels in different tissues. Here, we describe a detailed protocol for the quantification of the thyromimetic sobetirome using liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Assuntos
Acetatos/farmacocinética , Mimetismo Molecular , Fenóis/farmacocinética , Hormônios Tireóideos/farmacocinética , Acetatos/química , Animais , Cromatografia Líquida , Humanos , Redes e Vias Metabólicas , Camundongos , Estrutura Molecular , Fenóis/química , Espectrometria de Massas em Tandem , Hormônios Tireóideos/química , Distribuição TecidualRESUMO
Thyromimetics represent a class of experimental drugs that can stimulate tissue-selective thyroid hormone action. As such, thyromimetics should have effects on the hypothalamic-pituitary-thyroid (HPT) axis, but details of this action and the subsequent effects on systemic thyroid hormone levels have not been reported to date. Here, we compare the HPT-axis effects of sobetirome, a well-studied thyromimetic, with Sob-AM2, a newly developed prodrug of sobetirome that targets sobetirome distribution to the central nervous system (CNS). Similar to endogenous thyroid hormone, administration of sobetirome and Sob-AM2 suppress HPT-axis gene transcript levels in a manner that correlates to their specific tissue distribution properties (periphery vs CNS, respectively). Dosing male C57BL/6 mice with sobetirome and Sob-AM2 at concentrations ≥10 µg/kg/d for 29 days induces a state similar to central hypothyroidism characterized by depleted circulating T4 and T3 and normal TSH levels. However, despite the systemic T4 and T3 depletion, the sobetirome- and Sob-AM2-treated mice do not show signs of hypothyroidism, which may result from the presence of the thyromimetic in the thyroid hormone-depleted background.
Assuntos
Sistema Nervoso Central/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipófise/metabolismo , Glândula Tireoide/metabolismo , Acetatos/metabolismo , Animais , Sistema Hipotálamo-Hipofisário/patologia , Hipotireoidismo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenóis/metabolismo , Hipófise/patologia , Radioimunoensaio , Glândula Tireoide/patologia , Hormônios Tireóideos/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismoRESUMO
The blood-brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide. In mice, a systemic dose of sobetirome prodrug leads to a substantial â¼60-fold increase in brain distribution (Kp) of sobetirome compared to an equimolar systemic dose of the parent drug. The increased delivery of sobetirome to the brain from the prodrug was diminished by both pharmacological inhibition and genetic deletion of FAAH in vivo. The increased brain exposure of sobetirome arising from the prodrug corresponds to â¼30-fold increased potency in brain target engagement compared to the parent drug. These results suggest that FAAH-targeted prodrugs can considerably increase drug exposure to the CNS with a concomitant decrease in systemic drug levels generating a desirable distribution profile for CNS acting drugs.
Assuntos
Acetatos/farmacocinética , Amidoidrolases/metabolismo , Fenóis/farmacocinética , Pró-Fármacos/farmacocinética , Ativação Metabólica , Amidas/farmacocinética , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/deficiência , Amidoidrolases/genética , Animais , Ácidos Araquidônicos/metabolismo , Barreira Hematoencefálica , Química Encefálica , Endocanabinoides/metabolismo , Humanos , Hidrólise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Ácidos Oleicos/metabolismo , Especificidade de Órgãos , Alcamidas Poli-Insaturadas/metabolismo , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Hormônios Tireóideos/fisiologia , Distribuição TecidualRESUMO
Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.
Assuntos
Acetatos/química , Barreira Hematoencefálica/metabolismo , Etanolamina/química , Fenóis/química , Administração Oral , Amidas/química , Animais , Área Sob a Curva , Encéfalo/metabolismo , Ésteres/química , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Curva ROCRESUMO
There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.
Assuntos
Acetatos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Ésteres/farmacologia , Permeabilidade/efeitos dos fármacos , Fenóis/farmacologia , Pró-Fármacos/farmacologia , Acetatos/síntese química , Acetatos/química , Animais , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-AtividadeRESUMO
Sobetirome is one of the most studied thyroid hormone receptorâ ß (TRß)-selective thyromimetics in the field due to its excellent selectivity and potency. A small structural change-replacing the 3,5-dimethyl groups of sobetirome with either chlorine or bromine-produces significantly more potent compounds, both inâ vitro and inâ vivo. These halogenated compounds induce transactivation of a TRß-mediated cell-based reporter with an EC50 value comparable to that of T3, access the central nervous system (CNS) at levels similar to their parent, and activate an endogenous TR-regulated gene in the brain with an EC50 value roughly five-fold lower than that of sobetirome. Previous studies suggest that this apparent increase in affinity can be explained by halogen bonding between the ligand and a backbone carbonyl group in the receptor. This makes the new analogues potential candidates for treating CNS disorders that may respond favorably to thyroid-hormone-stimulated pathways.
RESUMO
The mononuclear Cu(I) complexes [LCu(I)(SSi(i)Pr3)] (L = 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos), 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes)) have been prepared by ligand displacement from [LCu(I)Cl] with (i)Pr3SiS(-). Both compounds are colorless, diamagnetic species and have been characterized structurally by X-ray crystallography. The compounds [(IMes)Cu(η(1)κ(S)-SC(O)CH3)] and [(triphos)Cu(η(1)κ(S)-SC(S)OCH3)] have been prepared in the context of synthesis aimed at [LCu(η(1)κ(S)-SCOS)] and [LCu(η(1)κ(S)-SCS2)] complexes, which are intended as synthons toward an analogue of the Mo(µ-OSCO)Cu intermediate proposed as occurring in the catalytic cycle of carbon monoxide dehydrogenase (CODH).
Assuntos
Complexos de Coordenação/química , Cobre/química , Metano/análogos & derivados , Compostos Organofosforados/química , Aldeído Oxirredutases/química , Cristalografia por Raios X , Ligantes , Metano/química , Modelos Moleculares , Complexos Multienzimáticos/químicaRESUMO
Oxidative addition of 1,2,11,12-tetrathia-5,8,15,19-tetra(N-methylamino)cycloicosane, the bis(disulfide) form of N,N'-dimethyl-N,N'-bis(2-mercaptoethyl)ethylenediamine (L-N2S2) to [Cu(MeCN)4][BF4] (2.5 eq.) in MeCN produces good yields of the decacopper cage compound [(Cu(II)(L-N2S2))4(µ2-Cu(I)(MeCN)2)2(µ3-Cu(I)(MeCN))4][BF4]6·2.25MeCN, [1][BF4]6·2.25MeCN. This mixed-valent hexacation shows idealized S4 point group symmetry and is composed of four [Cu(II)(L-N2S2] centers held in distorted four-coordinate environments and joined by µ2-Cu(I)(MeCN)2/µ3-Cu(I)(MeCN) ions that bridge their thiolate sulfur atoms. Each four-coordinate [Cu(II)(L-N2S2)] center is related to the other three by successive executions of the S4 operation. A dark violet color is observed for [1](6+) and attributed to a combination of metal-to-ligand (S), ligand (S)-to-metal, and, at lower energy, intermetal charge transfer transitions, as found for Cu5 cage compounds with a compositional relationship to [1](6+).
RESUMO
A synthesis of 1-(thioacetyl)triptycene (5), a convenient protected form of 1-(thiolato)triptycene [STrip](-), is described, a key transformation being the high yield conversion of tert-butyl 1-triptycenyl sulfide (8) to 5 by a protocol employing BBr(3)/AcCl. Syntheses of the two-coordinate copper(I) compounds [Bu(4)N][Cu(STrip)(2)], [Bu(4)N]10, and [(Cu(IMes)(STrip)] (13) proceed readily by chloride displacement from CuCl and [Cu(IMes)Cl], respectively. Reaction of 10 with Ph(3)SiSH or Me(3)SiI produces the heteroleptic species [Cu(STrip)(SSiPh(3))](-) (11) and [Cu(STrip)I](-) (12), detected by mass spectrometry, in mixture with the homoleptic bis(thiolate) anions. Structural identification by X-ray crystallography of the ligand precursor molecules 9-(thioacetyl)anthracene (4, triclinic and orthorhombic polymorphs), tert-butyl 9-anthracenyl sulfide (7), 5, and tert-butyl 1-triptycenyl sulfide (8) are presented. Crystallographic characterization of bis(9-anthracenyl)sulfide (3), which features a C-S-C angle of 104.0° and twist angle of 54.8° between anthracenyl planes, is also given. A crystal structure of [Bu(4)N][(STrip)], [Bu(4)N]9, provides an experimental measure of 144.6° for the ligand cone angle. The crystal structures of [Bu(4)N]10 and 13 are reported, the former of which reveals an unexpectedly small C-S···S-C torsion angle of â¼41° (average of two values), which confers a near "cis" disposition of the triptycenyl groups with respect the S-Cu-S axis. This conformation is governed by interligand π···π and CH···π interactions. A crystal structure of an adventitious product, [Bu(4)N][(Cu-STrip)(6)(µ(6)-Br)]·[Bu(4)N][PF(6)], [Bu(4)N]14·[Bu(4)N][PF(6)] is described, which reveals a cyclic hexameric structure previously unobserved in cuprous thiolate chemistry. The Cu(6)S(6) ring displays a centrosymmetric cyclohexane chair type conformation with a Br(-) ion residing at the inversion center and held in place by apparent soft-soft interactions with the Cu(I) ions.
Assuntos
Cobre/química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Compostos de Sulfidrila/química , Modelos Moleculares , Estrutura MolecularRESUMO
The structure of the title compound, [Ni(C(6)H(16)N(2))(2)]Br(2) or [Ni(Et(2)en)(2)]Br(2) (Et(2)en is asymmetric N,N-diethyl-ethylene-diamine), containing an Ni(II) atom (site symmetry ) in square-planar NiN(4) coordination, is described and contrasted with related structures containing Ni(II) in octa-hedral coordination with axial X(-) ligands (X(-) = variable anions). The dialkyl-ated N atom has an appreciably longer bond length to the Ni(II) atom [1.9666â (13)â Å] than does the unsubstituted N atom [1.9202â (14)â Å]. The Ni-N bond lengths in [Ni(Et(2)en)(2)]Br(2) are significantly shorter than corresponding values in tetra-gonally distorted [Ni(Et(2)en)(2)X(2)] compounds (X = (-)O(2)CCF(3), OH(2), or (-)NCS), which have a triplet ground state. The electronic configuration in these axially ligated [Ni(Et(2)en)(2)X(2)] compounds populates the metal-based d(x) (2) (-y) (2) orbital, which is Ni-N anti-bonding in character. Each Et(2)en ligand in each [Ni(Et(2)en)(2)](2+) cation forms a pair of N-Hâ¯Br hydrogen bonds to the Br(-) anions, one above and below the NiN(4) square plane. Thus, a ribbon of alternating Br(-) pairs and [Ni(Et(2)en)(2)](2+) cations that are canted at 65° relative to one another is formed by hydrogen bonds.