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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent agonist of the mu-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis- and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis- and trans-configurations with morphine and selective mu-peptide ligands PL-017 and D-TIPP, as well as the delta-selective peptide ligands TIPP (delta-antagonist, mu-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain mu- and delta-selectivity based on the presence of spatially distinct selectivity pockets among these ligands.

Cu2O is an efficient catalyst in the partial oxidation of propylene to acrolein, while propylene oxidation on CuO leads to complete combustion. The interaction of propylene at elevated temperature (>300 K) and elevated pressure (5 Torr) with cuprous and cupric oxide has been investigated with core level XPS, resonant photoemission, and temperature-programmed desorption. Reduction of the copper oxide surfaces was examined as a function of temperature and revealed that cupric oxide has a greater reactivity toward propylene oxidation than cuprous oxide (Ea = 5.9 versus 11.5 kcal/mol for cuprous oxide (24.7 and 48.1 kJ/mol)). This variable temperature oxidation of propylene was also monitored via core level and resonant photoemission and was found to occur by a similar mechanism on both surfaces. Reaction at lower temperature produces a surface intermediate which exhibits carbon 1s XPS peaks at 284.0 and 285.5 eV binding energy in a 2:1 intensity ratio. This is consistent with an allyl alkoxide surface specie...

The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is cleaved with neat volatile primary or secondary amines to give secondary or tertiary amines, respectively, in high yields and purity. Non-volatile secondary amines, thiols, and imidazole also cleave the alkyl chain efficiently to afford the expected products which can be readily purified by an ion-exchange resin work-up method.

The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is compatible with Grignard additions, stabilized Wittig, sodium borohydride reduction, reductive aminations, acylations and addition of various electrophiles, and Suzuki coupling. Cleavage of the resin-bound substrate with amines and other nucleophiles can provide diverse compound libraries.

Several of the key metabolites of mazapertine, a novel antipyschotic agent, were prepared in order to firmly establish their chemical structure and to obtain samples for biological testing. Hydroxymazapertine 3 was synthesized via a multi-step procedure starting from 5-fluoro-2-nitrophenol (8). Alcohol 4 was originally proposed for one of the major metabolites, but the confirmed structure after synthesis was isomer 20.

The enzyme glucokinase has recently been found to be largely responsible for glucose homeostatic responses of both the liver and pancreas. The mechanism(s) of these responses remains unknown but recent studies suggest that the intracellular localization of glucokinase, controlled by glucokinase regulatory protein, may be important. This protein is known to bind to and inhibit glucokinase in a phosphofructose-sensitive manner, and we present evidence for the interaction of these proteins with F-actin. Glucokinase regulatory protein gelled F-actin, and gelation was specifically inhibited by glucokinase and the regulatory protein effectors fructose-1-phosphate (F1P) and fructose-6-phosphate (F6P). These results suggest that glucokinase regulatory protein may play a role in metabolism-sensitive glucokinase localization in vivo.

Hindered rotation analogs of the antipsychotic mazapertine (1) were prepared. These compounds exhibited high affinity for the HT-1A receptor, but not for other serotonin or dopamine receptors. The related β-carboline structures were also sybthetized and were found to be potent 5-HT1A ligands.

Concurrent use of mephedrone (4-methylmethcathinone) (MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity following pretreatment with cocaine or MEPH than following pretreatment with saline. METH challenge produced greater locomotor activity following METH pretreatment than following saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bi-directional and did not extend to METH, suggesting the phenomenon is sensitive to specific psychostimulants.

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

The treatment of anxiety disorders remains an active area of research. Behavioural tests developed in the 1960s have been augmented by specific receptor binding assays. Selective modulation of these binding sites offers the hope that the abuse liability, sedation and ethanol interaction found with earlier drugs can be removed entirely or in part. Although most anxiolytic drug discovery continues to be centred on the neurotransmitters γ-aminobutyric acid (GABA) and serotonin (5-HT), research in other areas such as those involving cholecystokinin (CCK), corticotrophin releasing factor (CRF) and neuropeptide Y (NPY) also has promise for the future. This article reviews the primary and patent literature in the anxiolytic area for 1994 to the present.

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.

A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 microM), in which all have in vitro COX-1/COX-2 selectivity1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E2 production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED50 = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50 = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.

The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.

The five-fold differential cross section for the 12C(e,e'p)11B reaction was determined over a missing momentum range of 200-400 MeV/c, in a kinematics regime with Bjorken x > 1 and Q2 = 2.0 (GeV/c)2. A comparison of the results and theoretical models and previous lower missing momentum data is shown. The theoretical calculations agree well with the data up to a missing momentum value of 325 MeV/c and then diverge for larger missing momenta. The extracted distorted momentum distribution is shown to be consistent with previous data and extends the range of available data up to 400 MeV/c., 12 pages, 1 table and 3 figures for submission to Journal Physics G

Novel series of diaryl indenes and benzofurans have been shown to be potent and selective COX-2 inhibitors. A structure-activity relationship study suggests that the conversion of sulfones to sulfonamides affords potent, but slightly less selective COX-2 inhibitors, and that for benzofurans the 3-halo-4-methoxyphenyl sulfonamide analogs are more selective than the corresponding 4-fluorophenyl analog.

Prostaglandins are synthesized by the enzyme cyclooxygenase (COX), which is the target for nonsteroidal anti-inflammatory drugs (NSAIDs). Recently a second form of COX was discovered (COX-2) that is induced by inflammatory stimuli. The identification of an inducible form of COX led to the hypothesis that COX-2 is responsible for inflammatory prostaglandins, whereas the constitutive COX-I produces physiologically important prostaglandins, e.g., in stomach and kidney. Selective COX- 2 inhibitors have been shown to be anti-inflammatory but do not cause ulcers in the stomach or intestines. It is anticipated that drugs which selectively inhibit COX-2 will be superior anti-inflammatory agents with clear benefits over existing NSAIDs. In this review, the expression of human COX-I and COX-2 are discussed. A survey of the different chemical classes of COX-2 inhibitors with structure-activity relationships (SAR) and relevant pharmacological profiles are also presented.

Novel 4,5-diarylspiro[2.4]hept-5-enes, 6,7-diarylspiro[3.4]oct-6-enes, and 2,3-diarylspiro[4.4]non-2-enes have been synthesized and shown to be very potent inducible cyclooxygenase (COX-2) inhibitors with inhibition (IC 50 ) in the low nanomolar range and enzyme selectivity ratios as high as four orders of magnitude. The methyl sulfone spiro[2.4]hept-5-ene 1 (SC-58451) was found to be orally active (ED 50 = 0.3 mpk) in the rat adjuvant-induced arthritis model with no gastric lesions observed at 200 mpk.

Viral matrix proteins containing a highly conserved PPxY Late (L) domain motif are critical for efficient viral budding of several emerging RNA viruses. The L domain motif functions by recruiting host cell proteins necessary for separation of virus particles from the cell surface during the budding process. The conserved nature of the PPxY motif and its importance for viral egress make it an attractive drug target with potential broad spectrum antiviral activity. Here we describe a PPxY inhibitor capable of reducing viral budding of four highly lethal, category A RNA viruses: Ebola, Marburg, Lassa, and Junín viruses.

Polyelectrolyte hydrogels perform interest- ing physical and chemical changes, such as motility and bend in the presence of electric fields and interaction with ionic surfactants. We think that ionizable groups of poly- electrolyte hydrogels play a vital role in these environments. In this work, we prepared three anionic polyelectrolyte hy- drogels by two different routes, and micropipetts electrode was employed to determined negative potential in the gels. Our work showed that the gels reported herein all display a high degree of swelling with hydration and have a substan- tial negative potential in KCl solution and a simple mecha- nism was also described. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1319 -1321, 2003

We have measured the beam-normal single-spin asymmetry $A_n$ in the elastic scattering of 1-3 GeV transversely polarized electrons from $^1$H and for the first time from $^4$He, $^{12}$C, and $^{208}$Pb. For $^1$H, $^4$He and $^{12}$C, the measurements are in agreement with calculations that relate $A_n$ to the imaginary part of the two-photon exchange amplitude including inelastic intermediate states. Surprisingly, the $^{208}$Pb result is significantly smaller than the corresponding prediction using the same formalism. These results suggest that a systematic set of new $A_n$ measurements might emerge as a new and sensitive probe of the structure of heavy nuclei., 5 pages, 3 figures, accepted by PRL. v3: fixed one author name and affiliation, otherwise no change

Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC-6, ATG-7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.

Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes.

Lithiation of 8-chlorodibenz[b,f][1,4]oxazepine-10-tert-butylcarbamate (1) is described. Electrophilic substitution of the resulting N-Boc dibenzoxazepine α- lithioamine 2 with ketones, aldehydes, nitriles, iso-cyanates and imines, followed by an in-situ cyclization, gave fused carbamates 5–26, fused 2H-imidazol-2-ones 27–29, fused hydantoins 30–32, and fused ureas 33–35, respectively, in 11–66% yield.

Optical fibres bent in two mutually perpendicular planes have proven useful for randomizing illumination in light microscopes. These optical scramblers can increase the resolution and/or contrast obtained with several modes of light microscopy. Here, computer simulations are used to investigate several parameters affecting light randomization in curved optical fibres in order to further the theoretical basis for scrambler design. Light passing through 90 degrees bends of optical fibre of varying radii of curvature was modelled by ray tracing in two dimensions, and scrambling mechanisms were observed. The effects of varying the position and angle of entry of light on the phase and direction of propagation of the emergent light were determined. It was found that (a) thorough scrambling does not necessarily require high numerical aperture (NA) entry of light into the fibre, (b) considerable order persists after a single 90 degrees bend of an idealized fibre and (c) a higher degree of scrambling (at the cost of transmission efficiency) is achieved in more tightly curved fibres. The pathlength variations introduced by scrambling proved smaller than typical laser coherence lengths, requiring temporal scrambling (vibrating the fibre).

A series of 7,8-disubstituted guanosine derivatives was designed and prepared as potential B-cell-selective activators of the humoral immune response. These compounds were evaluated for their ability to act as B-cell mitogens and to augment the antibody response of B cells to sheep red blood cell (SRBC) challenge (adjuvanticity). In addition, they were tested for their ability to stimulate the natural killer (NK) cell response in murine in vitro cell assays. Certain of the compounds demonstrated in vivo activity when administered either intravenously, subcutaneously, or orally. Analogues with a medium-length alkyl chain (2-4 carbons, 5-7) on the 7-position of 7-alkyl-8-oxoguanosines were found to be particularly potent. Compounds bearing hydroxyalkyl, aminoalkyl, or substituted aminoalkyl substituents on this 7-position were weakly active. However, benzyl groups, including those substituted with heteroatoms (e.g., p-nitrobenzyl, 14), were active. Oxo, thioxo, and seleno groups on C-8 of the guanosine ring all imparted strong activity, whereas other larger substituents did not (e.g., N = CN). Stereochemical inversion of the 2'-hydroxyl on the ribose ring in this series, giving arabinose analogue 70, lessened activity. However, removal of the 2'-hydroxyl, either with (64) or without (73) removal of the 3'-hydroxyl, resulted in excellent activity and improved solubility; 64 also displayed good oral in vivo activity as well. A series of ketals involving the 2',3'-hydroxyls were prepared; certain of the nonpolar ketals (e.g., 48) were remarkably active, pointing to an ancillary hydrophobic binding region that can augment activity. 5'-Phosphate derivative 57 was fairly active, and acyclovir analogue 90 displayed good NK-selective activity: other N-9 sugar mimetics were also active (97-104), although this activity did not carry over into the human B-cell assay. A total of 80 compounds were prepared and evaluated for their immunostimulating activity. Within this group, compounds could be divided into those that were active in all three assays, those that displayed some measure of selectivity for the adjuvanticity assay, and those that preferentially activated NK responses. Because of its overall biological profile and ease of synthesis, 7-allyl-8-oxoguanosine (6; loxoribine, RWJ-21757) was chosen for further development. It is among the most potent compounds evaluated in the three biological assays.

A one-pot synthesis of sulfonamides from methyl sulfones has been developed. Treatment of methyl sulfones with base and trialkylboranes gave the corresponding rearranged sulfinic acid salts which were converted to sulfonamides during oxidative-amination workup.

Polyhydroxylated pyrrolidines and piperidines were prepared by the double reductive amination of dicarbonyl sugars with primary amines and NaCNBH 3 in MeOH. Stereocontrol in these reactions depended on the nature of the amine and dicarbonyl sugar. For example, 5-keto-D-fructose (7) gave three pyrrolidine stereoisomers, with the N-alkylated 2,5-anhydro-2,5-imino-D-glucitol predominating. Under similar reaction conditions with benzhydrylamine, 5-keto-D-glucose (20) afforded a 96:4 mixture of piperidines favoring D-gluco 25A, whereas 5-keto-D-mannose (6) produced a 67:33 mixture enriched in D-manno isomer 40. This method allowed for the direct and relatively short synthesis of 1-deoxynojirimycin (DNJ, 1) and 1-deoxymannojirimycin (DMJ, 5) and N-alkylated derivatives thereof. Similar reactions with O-protected 5-keto-D-glucose derivatives 21 and 22 were less stereoselectivite and lower yielding

Substituting nitrogen for carbon in the pyridinylphenylmethyl analogs of SC-50560 proved to be detrimental, however, the two phenylpyridinylmethyl analogs of SC-50560 retained their potencies. Of these two analogs, SC-52458 was found to have superior in vivo properties.

The d(e,e'p) cross section at a momentum transfer of 3.5 (GeV/c)^2 was measured over a kinematical range that made it possible to study this reaction for a set of fixed missing momenta as a function of the neutron recoil angle theta_nq and to extract missing momentum distributions for fixed values of theta_nq up to 0.55 GeV/c. In the region of 35 (deg), 5 pages, 2 figures

Isoquinoline N-oxide ( 2 ) reacts with 18 O-enriched tosyl chloride to furnish 18 O-labeled 4-tosyloxy-isoquinoline ( 4 ), which was assessed for oxygen isotopic enrichment by NMR and mass spectrometry. The 30–45% 18 O incorporation at the bridging oxygen is inconsistent with a high level of the intramolecular tight-ion-pair (“sliding”) mechanism. A combination of two intramolecular mechanisms is probably operative.

The depressor activity of a novel nonpeptidic angiotensin II (AII) receptor antagonist, SC-51316 (2,5-dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4 '- yl]-methyl]-3H-1,2,4-triazol-3-one), is described. In anesthetized, ganglion-blocked rats, intravenous administration of SC-51316 inhibited the pressor response to an infusion of AII. To determine antihypertensive efficacy, conscious, spontaneously hypertensive rats were administered SC-51316 (30 mg/kg intragastrically) daily for 5 days. Blood pressure was reduced in a similar manner to that observed with the angiotensin converting enzyme inhibitor enalapril (10 mg/kg intragastrically). SC-51316 had no effect on heart rate. In conscious, sodium-deficient dogs, administration of SC-51316 (30 mg/kg orally) or enalapril (10 mg/kg orally) lowered blood pressure similarly over a 24 h observation period. Thus, SC-51316 antagonizes the activity of AII in vivo and is an orally active, antihypertensive agent.

The surmountable (competitive) N 1 -(2-methylphenyl)-2H-imidazol-2-one angiotensin II receptor antagonist SC-54628 is converted to an insurmountable (noncompetitive) antagonist SC-54629 by the addition of a methyl group at the 6-position of the phenyl ring.

A series of 5-[1-[4-[(4,5-disubstituted-1H-imidazol-1-yl)methyl]- substituted]-1H-pyrrol-2-yl]-1H-tetrazoles and 5-[1-[4-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-substituted]- 1H-pyrrol-2-yl]-1H-tetrazoles were investigated as novel AT1-selective angiotensin II receptor antagonists. Computer-assisted modeling techniques were used to evaluate structural parameters in comparison to the related biphenyl system. New synthetic procedures have been developed to prepare the novel compounds. The best antagonists in this series had IC50 values (rat uterine membrane receptor binding) in the 10(-8) M range and corresponding pA2 in isolated organ assay (rabbit aorta rings). Structure-activity relationships indicate some similarities with the finding in the biphenyl system. Substitution on the pyrrole ring modulates activity. Compound 5 antagonized angiotensin-induced blood pressure increase when administered to conscious rat at 30 mg/kg per os.

Piperazinyl benzamidines were prepared and found to bind to the rat delta (δ) opioid receptor. The most active compounds had a N,N -diethylcarboxamido group and a N -benzyl piperazine. The most potent among these was N,N -diethyl-4-[4-(phenylmethyl)-1-piperazinyl][2-(trifluoromethyl)phenyl]iminomethyl]benzamide ( 27 ) with a 1.22 nM K i for the rat δ opioid receptor and ca. 1000× selectivity relative to the μ opioid subtype.

The electric form factor of the neutron was determined from studies of the reaction ${}^{3}\stackrel{\ensuremath{\rightarrow}}{\mathrm{He}}(\stackrel{\ensuremath{\rightarrow}}{e},{e}^{\ensuremath{'}}n)pp$ in quasielastic kinematics in Hall A at Jefferson Lab. Longitudinally polarized electrons were scattered off a polarized target in which the nuclear polarization was oriented perpendicular to the momentum transfer. The scattered electrons were detected in a magnetic spectrometer in coincidence with neutrons that were registered in a large-solid-angle detector. More than doubling the ${Q}^{2}$ range over which it is known, we find ${G}_{E}^{n}=0.0236\ifmmode\pm\else\textpm\fi{}0.0017(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}0.0026(\mathrm{syst})$, $0.0208\ifmmode\pm\else\textpm\fi{}0.0024\ifmmode\pm\else\textpm\fi{}0.0019$, and $0.0147\ifmmode\pm\else\textpm\fi{}0.0020\ifmmode\pm\else\textpm\fi{}0.0014$ for ${Q}^{2}=1.72$, 2.48, and $3.41\text{ }\text{ }{\mathrm{GeV}}^{2}$, respectively.