Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tetrahydronaphthalenes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1999

1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)alkyl]piperazines and their analogues: influence of the stereochemistry of the tetrahydronaphthalen-1-yl nucleus on 5-HT1A receptor affinity and selectivity versus alpha1 and D2 receptors. 5.

Some 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their absolute configuration was determined by chemical correlation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and alpha1 receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicated that, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between (-)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry, instead, influenced the selectivity: all (-)-enantiomers displayed affinity values higher than those of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinity values higher than those of (-)-isomers at alpha1 receptors. As a result of this trend, it is not possible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (>/=250-fold) versus both D2 and alpha1 receptors. Furthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [35S]GTPgammaS binding assay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.

Animals↗
PubMed2004

Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents.

A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin (5-hydroxytryptamine, 5-HT) 5-HT7, 5-HT(1A), and 5-HT(2A) receptors was measured by in vitro binding assays. In relation to 5-HT7 receptor affinity, receptor binding studies indicated that (i) the optimal alkyl chain length was five methylenes, (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl nucleus was preferred, and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a crucial role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), and 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7 receptor-mediated relaxation of substance P-induced guinea pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists and compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist. Among the compounds presented here, it emerged that 44 was identified as a potent 5-HT7 receptor agonist (Ki = 0.22 nM, EC50 = 2.56 microM), endowed with selectivity over 5-HT(1A) and 5-HT(2A) receptors (200-fold and >1000-fold, respectively).

Amides↗
PubMed1990

Novel [(diazomethyl)carbonyl]-1,2,3,4-tetrahydronaphthalene derivatives as potential photoaffinity ligands for the 5-HT1A receptor.

The photolabile (diazomethyl)carbonyl function was introduced into the 8-position of 2-(N,N-di-n-propyl-amino)-1,2,3,4-tetrahydronaphthalene in three ways, resulting in the ether 8-[[(diazomethyl)carbonyl]methoxy]-2-(N,N-di-n-propylamino)-1,2,3,4- tetrahydronaphthalene (2), the ester 8-(diazoacetoxy)-2-(N,N-di-n-propyl-amino)-1,2,3,4- tetrahydronaphthalene (3), and the ketone 8-[(diazomethyl)carbonyl]-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (4). Specific binding of these compounds at the 5-hydroxytryptamine1A sites in rat brain membranes labeled with 1 nM [3H]-8-hydroxy-2-(N,N-di-n-propylamino)- 1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) showed IC50 values of ca. 75, 125, and 25 nM, respectively, for the three compounds. Photolysis of methanolic solutions of 2-4 in the absence of receptor proteins lead in each case to an abundance of Wolff-rearranged products. In the case of ether 2, subsequent beta-elimination to 8-OH-DPAT removed this compound from serious consideration as a photoaffinity ligand. Ester 3 and ketone 4 were photolysed in vitro. Whereas ester 3 was ineffective in decreasing the specific binding of [3H]-8-OH-DPAT, ketone 4 decreased 40% of the specific binding of [3H]-8-OH-DPAT in the presence (but not the absence) of ultraviolet light. Thus this ketone emerges from these studies as a good candidate for a photoaffinity label for the 5-hydroxytrypatamine1A receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity.

Certain novel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 microM concentrations in rodent brain tissue. This effect on TH was blocked by the putative sigma-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory sigma-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (+/-)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene ([3H](+/-)-4). trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known sigma or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known sigma or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(-)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates sigma-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.

Animals↗
PubMed2006

Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

Administration, Topical↗
PubMed1978

Inhibition of apomorphine-induced behaviors by derivatives of 2-amino-1, 2, 3, 4-tetrahydronaphthalene.

In order to elucidate the pharmacological properties of a series of 1-phenyl-2-aminopropane and 2-amino-1, 2, 3, 4-tetrahydronaphthalene derivatives, their ability to inhibit a number of apomorphine-induced behaviors was investigated. Several members of the series under study were potent inhibitors of apomorphine-induced pecking behavior in pigeons, emesis in dogs, and gnawing in rats. In addition, these compounds were able to inhibit responding in self-stimulating rats and to a lesser degree counteracted the depression of the linguomandibular reflex induced by 5, 6-dihydroxy-2-dimethylamino-1, 2, 3, 4-tetrahydronaphthalene (M-7) in the cat. The most effective member of the experimental compounds was N-methyl-5, 8-dimethoxy-2-amino-1, 2, 3, 4-tetrahydronaphthalene; however, neither this material nor any of the related structures were able to inhibit apomorphine-induced rotational behavior in substantia nigra lesioned rats. The possibility that the more effective members of the experimental series are able to inhibit certain apomorphine-induced behaviors by stimulation of central alpha adrenergic receptors is discussed.

Animals↗
PubMed1976

Synthesis and dopaminergic activity of (+/-)-, (+)-, and (-)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene.

In an effort to identify further the structural requirements for central dopamine receptor agonists, some monohydroxyl analogs of the known agonist 5,6-dihydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene were synthesized. They were examined for production of emesis in dogs and stereotyped behavior in rats. The most potent was 5-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, which was more potent than apomorphine but less so than the dihydroxyl analog. The two enantiomers of the monohydroxyl analog were synthesized by conventional methods from an optically active intermediate, 2-benzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene. The resolution of this amine was performed with the aid of mandelic acid. Dopaminergic activity was found to be confined to the levo enantiomer. Requirements for both substitution and chirality in the tetralines were found to correspond closely to those known for the dopaminergic aporphines.

2-Naphthylamine↗
PubMed2001

Melatonin receptor agents: synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (+/-)-N-[[2[(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide.

In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (+/-)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5 was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (-)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2.

Cell Line↗
PubMed1998

Modelling of residual variability in toxicokinetic studies with sparse sampling: the case of tetrahydronaphthalene.

The present study describes the kinetics of tetrahydronaphthalene in male and female rats (five animals per dose per sex) at three dose levels (15, 50, and 150 mg/kg daily). Plasma concentration measurements were performed in the course of a subacute toxicity study of 28 days duration in an enriched study design. Two blood samples per animal were taken at different time points after application at day 1 and 16 (150 mg/kg daily) and at day 3 and 18 (15 and 50 mg/kg daily), respectively. Tetrahydronaphthalene was assayed by gas chromatography-mass spectrometry (GC-MS) after extraction. The data of plasma concentration time were analysed using non-linear mixed effects modelling as implemented in NONMEM. The structural model with the best fit employed one compartment kinetics with instantaneous drug input. Interindividual variability in both k and V was found to be very small [k, 0.201 h(-1), 0.013; V, 16.19 (kg), 1.77; population mean and SE]. No unequivocal evidence of dose dependence could be found. The kinetic parameter with the highest extent of variability was the extent of bioavailability which showed an coefficient of variation (CV) of 96%. Both gender and dose had no influence on the variability. The present approach is concluded to offer more insight into the relationship between dose, concentration and effect and into factors which explain variability in kinetics without additional testing or additional animals. Proposals for a refined sampling schedule are made.

Animals↗
PubMed1994

Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.

Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

Animals↗
PubMed1981

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.

Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.

Animals↗
PubMed1982

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 2. Derivatives of a hypotensive-positive inotropic agent.

Seven derivatives of 2-[[2-(3,4-dihydroxyphenyl)-1-methylethyl]amino]-6,7-dihydroxy-1,2,3,4- tetrahydronaphthalene, an inotropic agent which also causes a decrease in blood pressure, were synthesized and tested for inotropic potency, cardioselectivity, and inotropic selectivity. The derivatives were designed to explore whether catechol moieties and rigid rotamers of dopamine are necessary for the activity which was found in the parent compound. The derivatives had phenolic functions in place of catechols, and they had phenethylamine in place of the tetrahydronaphthalene moiety. In no case was the profile of activity of the parent compound duplicated in the derivatives.

Animals↗
PubMed1995

Covalent affinity labeling of brain catecholamine-absorbing proteins using a high-specific-activity substituted tetrahydronaphthalene.

The recently described catecholamine-absorbing proteins (CATNAPs) are expressed within the CNS and have been shown to participate in neurochemical processes involving dopamine and several structurally related catecholamines. Specifically, CATNAPs have been implicated in participating directly in oxidative mechanisms involving reactive species (such as free radicals) derived from these compounds. Toxic free radicals generated from endogenous catecholamines have been identified as a major cause of neuronal tissue injury and are implicated in several disease processes. CATNAPs were first identified by their ability to react covalently with tritiated dopaminergic compounds, incorporating low levels of radioactivity under appropriate reaction conditions. The biochemical characterization of CATNAPs has until now been hampered by the lack of a suitable high-specific-activity probe to allow the rapid detection of these proteins. We describe here the synthesis and labeling characteristics of a high-specific-activity substituted tetrahydronaphthalene derivative (6-hydroxy-[125I]iodo-[N-(N-2',4'- dinitrophenyl)aminopropyl]-2-amino-1,2,3,4-tetrahydronaphthalene), which covalently incorporates into CATNAPs with the same tissue distribution, molecular weight patterns, and pharmacology as observed for the previously studied tritiated catecholamines. This compound greatly enhances the detection of CATNAPs and will facilitate further biochemical characterization of these proteins.

Absorption↗
PubMed2001

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: a new class of potent and selective 5-HT(1A) receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines.

The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.

Animals↗
PubMed1999

Directed, DDQ-Promoted Benzylic Oxygenations of Tetrahydronaphthalenes.

Positional preferences for para benzylic oxygenation of tetrahydronaphthalenes by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-aqueous dioxane were investigated by comparing the tetralone products from 6-hydroxy-7-methoxy- and 6-acetoxy-7-methoxy-1,2,3,4-tetrahydronaphthalene. The directing influence by an aromatic substituent on para benzylic oxygenation was in the order OH > OMe > OAc. Consistent with this finding were results obtained from lignan analogues. Treatment of (+)-beta-conidendryl alcohol with DDQ in dry dioxane resulted in the intramolecular bridging by one of two primary hydroxy groups to the benzylic position, giving an oxabicyclo[3.2.1]octane. Similar treatment of (+)-dimethyl-beta-conidendryl alcohol resulted in bridging by the alternate primary hydroxyl group to the benzhydrylic carbon giving an isomeric oxabicyclo[3.2.1]octane.

Journal Article↗