Naphthalene Analogues Research Articles

4-(tetralin-1-yl)- and 4-(naphthalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as sigma receptor ligands with agonist sigma2 activity.

Several 1-cyclohexylpiperazine derivatives related to sigma(2) receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (33, K(i) = 0.34 nM) were synthesized and tested in radioligand binding assays, to attempt a structure-affinity relationship study. Intermediate alkyl chain length and methoxyl group position on the tetralin nucleus were varied. A few naphthalene analogues were also prepared. High affinities were found in sigma(2) receptor binding for almost all compounds, some of which displayed K(i) values in subnanomolar range, but low sigma(2)/sigma(1) selectivities were found. The highest sigma(2) affinities were displayed by compounds with an intermediate alkyl chain of three (32 and 43) or five methylenes (39 and 46). Quite high sigma(1) receptor affinity was found for compounds with a four-methylene chain; 36 (K(i) = 0.036 nM) and 45 (K(i) = 0.22 nM) displaying good sigma(1)/sigma(2) selectivity (406- and 139-fold, respectively). Moreover, homologues of compound 33 displayed also satisfactory selectivities over dopamine D(2)-like, serotonin 5-HT(3), and adrenergic alpha(1) receptors. These compounds and a few others were tested in the inhibition of the electrically evoked contractions in guinea pig bladder and were demonstrated to be full sigma(2) agonists. The activity values correlated well to the affinity scale (EC(50) in microM range). 33 and related compounds are proposed as a class of potential antineoplastic and PET diagnosis agents.

Steric-controlled excimer formation in naphthalene analogues of chalcone

Naphthalene analogues of chalcone (typical vinylarenes) are well known for their intramolecular charge transfer (CT) process. The all four possible isomers NC1, NC2, NC3 and NC4 were observed to give structure-less broad CT bands, whereas, excimer formation at higher concentration was reported only for NC4 [Res. Chem. Intermed. 25 (1999) 903]. However, conventional GMMX calculation data reveals that the naphthalene portion of all the isomers are planar, hence, excimer emission is expected from all of them, i.e., if NC4 can form an excimer, then the rests are also capable of doing it. In this paper we have actually succeeded in resolving the excimer peaks for all these four isomers by optimization of concentration, though the extent of excimer formation was observed to be the maximum for NC4. These differential tendencies of excimer formation can be explained by the change in extent of intermolecular stacking interaction of the naphthalene moieties. Variation occurs here due to steric perturbation arising from the specific orientation of the near resident non-planar aroyl component with respect to the naphthalene moiety.

Synthesis of Tetrahydrocannabinols Based on an Indirect 1,4‐Addition Strategy.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Energetics, electronic structures and geometries of naphthalene, quinoline and isoquinoline analogues of 1,2-didehydrobenzene

B3LYP/cc-pVTZ electronic structure calculations employed in conjunction with additive corrections derived from experimental data for 1,2-didehydrobenzene predict the standard enthalpies of formation of 1,2- and 2,3-didehydronaphthalenes to be equal to 121.0 and 123.7 kcal mol−1, respectively. The corresponding singlet-triplet splittings amount to 40.1 and 35.4 kcal mol−1. The positional dependence of both of these quantities is preserved in those didehydroquinolines and didehydroisoquinolines in which the didehydrogenation sites are separated by at least one carbon from the heteroatoms. The effect of the adjacent heteroatoms on the singlet-triplet splittings is significantly more pronounced than that on the standard enthalpies of formation. Test G3 calculations on 2,3-didehydronaphthalene confirm the reliability of the additive correction scheme in the prediction of properties of annelated analogues of 1,2-didehvdrobenzene. Such a scheme opens an avenue to facile electronic structure calculations on didehydrogenation reactions of polycondensed heterocyclic compounds with six-membered rings.

Synthesis of tetrahydrocannabinols based on an indirect 1,4-addition strategy.

The synthetic procedure presented for the preparation of the title compounds requires 1,4-addition of bulky cuprates to cyclohexenones and subsequent reaction with electrophiles. However, the enolates generated by BF(3).OEt(2)-assistance suffer from lack of nucleophilicity. To circumvent this problem, we developed an indirect method consisting of the following three steps: (1) iodination of the cyclohexenones at the alpha position; (2) BF(3).OEt(2)-assisted 1,4-addition of cuprates (Ar(2)Cu(CN)Li(2), Ar = aryl) followed by quenching the enolates with water; (3) reaction of the alpha-iodo-beta-aryl-cylohexanones thus formed with EtMgBr to generate magnesium enolates. The enolates thus generated in this way showed a high reactivity toward ClP(O)(OEt)(2) to furnish enol phosphates. The aforementioned procedure was also applied to a synthesis of optically active Delta(9)-tetrahydrocannabinol. In addition, a naphthalene analogue of the latter compound was also synthesized in a similar way.

Characterisation of human melatonin mt 1 and MT 2 receptors by CRE-luciferase reporter assay

A cyclic AMP response element (CRE)-luciferase reporter gene assay was used to characterise the functional responses of human melatonin mt 1 and human melatonin MT 2 receptors, stably expressed in the human embryonic kidney cell line HEK293, to a series of six naphthalenic analogues of melatonin. By comparison to the observed melatonin-mediated inhibition of stimulated luciferase levels the naphthalenic series was identified as comprising agonists, partial agonists and one antagonist of melatonin mt 1 and melatonin MT 2 receptor function. Three of the agonist/partial agonist members of this series were also identified as displaying a functional selectivity for the melatonin MT 2 receptor. Competitive displacement of 2-[ 125I]iodomelatonin binding to the ovine pars tuberalis melatonin ML 1 receptor demonstrated a close correlation to the observed functional luciferase responses of the human melatonin mt 1 receptor. We conclude that the CRE-luciferase reporter gene assay provides an effective functional screening method for the pharmacological characterisation of human melatonin receptor subtypes.

Intramolecular Charge Transfer in Naphthalene Analogues of Chalcone#

Intramolecular charge transfer (ICT) bands were observed in the emission spectra of naphthalene analogues of chalcones of type A, B and C. In C, a naphthalene excimer band was also observed because of increased coplanarity in such molecules. Neither any phosphorescence band nor any triplet transient could be detected from either of these molecules.

Naphthalene uptake by a Pseudomonas fluorescens isolate

TThe uptake of naphthalene has been investigated in the metabolizing cells of Pseudomonas fluorescens utilizing [1-14C]naphthalene. The uptake displayed an affinity constant (Kt) of 11 μM and a maximal velocity (Vmax) of 17 nmol·h-1·mg-1 cellular dry weight. Naphthalene uptake was not observed in a mutant strain, TG-5, which was unable to utilize naphthalene as a sole source of carbon for growth. Uptake was significantly inhibited (~90%) by the presence of growth-inhibiting levels of either azide or 2,4-dinitrophenol and was sensitive to the presence of structural analogues of naphthalene. The intracellular levels of ATP were not significantly reduced by the presence of either azide or 2,4-dinitrophenol. The presence of alpha-naphthol was found to noncompetitively inhibit naphthalene uptake, displaying a Ki of 0.041 μM. It is concluded that the first step in the utilization of naphthalene by Pseudomonas fluorescens is its transport into the cell by a specific energy-linked transport system.Key words: naphthalene, PAH, biodegradation, transport.

Effects of two melatonin analogues, S-20098 and S-20928, on melatonin receptors in the pars tuberalis of the rat.

By using quantitative autoradiography, we studied the effects of two drugs related to melatonin on the 2-(125)I-melatonin binding in the pars tuberalis (PT) of rats. The drugs tested were two naphthalenic analogues of melatonin, S-20098 (N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide), an agonist, and S-20928 (N-[2-(1-naphthyl) ethyl] cyclobutyl carboxamide), a putative antagonist. Melatonin (s.c. and i.p.), S-20098 (s.c.), and S-20928 (i.p.) were injected 4 hr before sacrifice. Acute administration of both melatonin and S-20098 decreased melatonin receptor density. In contrast, the putative antagonist S-20928, at a low dose (1 mg/kg), was ineffective on melatonin receptors. It neither affected the 2-(125)I-melatonin specific binding observed in the control group nor did it prevent the decrease in binding induced by melatonin when injected 5 min before the hormone. At a high dose (10 mg/kg), S-20928 totally blocked the effect of melatonin on melatonin receptor density and induced a decrease in binding capacity as melatonin did when injected alone. These results indicate that in the rat pars tuberalis, the melatonin agonist, S-20098, is able to down-regulate melatonin receptors, whereas S-20928 seems to behave as a partial agonist.

Synthesis and structure–activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands

A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure–activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n propyl urea derivative (27) is a very potent ligand at this receptor (pKi=14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This molecule, compound 12, or N-[2-(1-naphthyl)ethyl]cyclobutyl carboxamide has been selected for preclinical development.

Post-column derivatization for fluorescence and chemiluminescence detection in capillary electrophoresis

Instrumental developments and applications of post-column derivatization for fluorescence and chemiluminescence detection in capillary electrophoresis (CE) are reviewed. Various systems to merge the reagent solution with the separation medium have been developed, including coaxial capillary reactors, gap reactors and free solution or end-column systems. For all reactor types the geometry of the system, as well as the method to propel the reaction mixture (by pressure or by voltage) appeared to be critical to preserve the separation efficiency. Plate numbers of over 100 000 could be realised with different reactors. The strict requirements on the rate of post-column derivatization reactions to be applied in CE limit the number of different reagents that have been used. For fluorescence detection, with laser or lamps as the excitation source, so far mainly o-phthalaldehyde and its naphthalene analogue have been used as reagent. Derivatization systems that are based on complexation reactions also showed good promise for application in CE. Detection limits could be obtained that were comparable to those obtained after pre-column derivatization. Various reagents for chemiluminescence detection (e.g. the luminol and peroxyoxalate systems) have been studied. The often complicated chemistry involved made application of these reagents in CE even more difficult. Results obtained so far, in terms of sensitivity, have not been up to expectation, with detection limits usually in the order of μmol l −1.

A Study of the Bioconversion Potential of the Fungus Bjerkandera Adusta with Respect to a Production of Chlorinated Aromatic Compounds

Fluoro-labelled substrates and membrane inlet mass spectrometry (MIMS) was used to test the bioconversion potential of the white-rot fungus Bjerkandera adusta with respect to a production of novel halogenated aromatic compounds. The presence of a fluorine atom on the aromatic ring of possible precursors to the well-known metabolites, 3-chloro-4-methoxybenzaldehyde and 3,5-dichloro-4-methoxybenzaldehyde, did not influence the metabolism and they all gave mixed chloro-fluoro-methoxybenzaldehydes; however, we were unable to produce any new chlorinated compounds. Neither supplementation of anisole, benzaldehyde, veratryl alcohol, the naphthalene analogs nor methyl-substituted benzaldehydes resulted in a production of detectable amounts of the corresponding chlorinated products. Apparently, only hydroxybenzaldehydes and/or methoxybenzaldehydes are chlorinated by the halogenating system. Experiments where an aromatic alcohol, aldehyde, or the analog acid was supplemented gave qualitatively and quantitatively similar membrane inlet mass spectra suggesting that oxidases and reductases maintain a stoichiometric ratio between these compounds. Several cases of hydroxylation and/or methoxylation of the substrates were also observed.

Naphthalene uptake by a Pseudomonas fluorescens isolate.

The uptake of naphthalene has been investigated in the metabolizing cells of Pseudomonas fluorescens utilizing [1-14C]naphthalene. The uptake displayed an affinity constant (Kt) of 11 microM and a maximal velocity (Vmax) of 17 nmol.h-1.mg-1 cellular dry weight. Naphthalene uptake was not observed in a mutant strain, TG-5, which was unable to utilize naphthalene as a sole source of carbon for growth. Uptake was significantly inhibited (approximately 90%) by the presence of growth-inhibiting levels of either azide or 2,4-dinitrophenol and was sensitive to the presence of structural analogues of naphthalene. The intracellular levels of ATP were not significantly reduced by the presence of either azide or 2,4-dinitrophenol. The presence of alpha-naphthol was found to noncompetitively inhibit naphthalene uptake, displaying a Ki of 0.041 microM. It is concluded that the first step in the utilization of naphthalene by Pseudomonas fluorescens is its transport into the cell by a specific energy-linked transport system.

1,8-bis(hydroxymethyl)anthracene.

Anthracene-1,8-dimethanol, C16H14O2, crystallized in the centrosymmetric space group P21/n. The anthracene core is nearly planar and shows good agreement with the anthracene core of anthracene-1,8-dicarboxylic acid. The geometric disposition of the hydroxymethyl groups and the values of the hydrogen-bond parameters are strikingly similar to those in the naphthalene analog. As in that structure, each hydroxyl group participates both as a donor and acceptor in an infinite zigzag chain of hydrogen bonds which propagates along the [010] direction. Moreover, the disposition of the entire molecule in the cell of the present compound is also strikingly similar to that of the naphthalene analog in its cell.

Preliminary communication A novel class of heterocyclic liquid crystals with broad smectic C phase

A successful approach in molecular design through fusing aromatic/heterocyclic rings for broadening the smectic C (SmC) phase and the synthesis of the first heterocyclic liquid crystalline (LC) molecules containing 3,7-disubstituted quinoline with one of the widest SmC phases are reported. Their naphthalene analogues are compared. The nitrogen atom in quinoline system introduces attractive forces to aid the formation of the tilted SmC phase and the flexible chain length also influences the tilted SmC phase effectively.

Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl.

10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5, 10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxyl-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5- methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the EO771 mammary adenocarcinoma in mice, 9a was less active than MTX.

Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

(Aminoalkyl)indole isothiocyanates as potential electrophilic affinity ligands for the brain cannabinoid receptor.

A series of (aminoalkyl)indole compounds, naphthalene analogs of pravadoline (1), has been shown to exhibit cannabinoid agonist activities such as antinociception in animals, inhibition of adenylate cyclase in brain membranes, and binding to the cannabinoid receptor. These pravadoline analogs were selected for the preparation of potential electrophilic affinity ligands based on the synthesis of isothiocyanate derivatives. One isothiocyanatonaphthalene derivative (8) displaced [3H]CP-55940 binding to a rat brain P2 membrane preparation with an IC50 of 690 nM, which was 10-fold less potent than the parent molecule (IC50 = 73 nM). Isothiocyanate substitution at various positions on the naphthalene moiety of the desmethyl analog 10 gave compounds that displaced [3H]CP-55940 with IC50 values between 400 and 1000 nM, compared with 46 nM for the parent compound 10. However, 6-isothiocyanato substitution on the indole ring of the desmethyl analog provided isothiocyanate 12 that displaced [3H]CP-55940 binding with an IC50 and 160 nM. After pretreatment of brain membranes with this high-affinity isothiocyanato ligand followed by washing out the ligand, the membranes were depleted of 90% of the cannabinoid receptor binding capacity. Loss of receptor binding capacity was half-maximal at 300 nM of the derivative under standard assay conditions. As a control, pretreatment with the parent compound at concentrations that were 20 times the Kd failed to alter subsequent binding activity. This study demonstrates that an isothiocyanato (aminoalkyl)-indole (12) can behave as an affinity ligand which binds irreversibly to the cannabinoid receptor in brain and which precludes subsequent binding of the cannabinoid ligand [3H]CP-55940.

17O and 11B NMR spectroscopic study of substituted benzo[d]‐2,2‐difluoro‐1,3,2‐oxoniaoxaboratins

Abstract17O NMR data are reported for 10 benzo[d]‐2,2‐difluoro‐1,3,2‐oxoniaoxaboratins derived from various ortho‐hydroxyacetophenones and for 2,2‐difluoro‐1,3,2‐oxoniaoxaboratins derived from related hydroxyacetyl naphthalenes and hydroxybenzophenones. The signal for the carbonyl‐like oxygen for these compounds is substantially shielded and appears at 288 ± 22 δ. The single bonded oxygen signal for the 1,3,2‐oxoniaoxaboratins appears at 122 ± 6 δ, except for the naphthalene analogs, whose signal appears at 146 ± 10 δ. The 11B NMR signal for these compounds is insensitive to structural changes and appears at 0.85 ± 0.25 δ. © 1995 John Wiley & Sons, Inc.

A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.