[Ethylamine derivatives of methane and norpinane: 2-(3-methyl)ethylamine and derivatives of 6,6-dimethyl-2-norpinene-2-ethylamine (nopylamine)].
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Anti-Inflammatory Agents↗
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Results for “Ethylamines”
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Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H1-receptor agonists.
To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H1-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine.
Animals↗
Effects of chronic administration of beta-(3,4-dimethoxyphenyl)-ethylamine and beta-(3,4,5-trimethoxyphenyl)-ethylamine on the climbing rope performance of rats.
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Abdomen↗
Ring opening photoreactions of cytosine and uracil with ethylamine.
The photochemical reactions of cytosine (Cyt) and uracil (Ura) with ethylamine, an analog of the side chain of the amino acid lysine, have been studied. After irradiation of Cyt in aqueous ethylamine at lambda = 254 nm, N-(N'-ethylcarbamoyl)-3-aminoacrylamidine (Ia) and N-(N'-ethylcarbamoyl)-3-ethylaminoacrylamidine (Ib) were isolated as products, while irradiation of Ura gave N-(N'-ethylcarbamoyl)-3-aminoacrylamide (IIa) and N-(N'-ethylcarbamoyl)-3-ethylaminoacrylamide (IIb) as products. Studies in which Ia and IIa were incubated with ethylamine at various pH values indicate that Ib and IIb are secondary products produced via thermal reactions of Ia and IIa with ethylamine. Heating of Ia and Ib leads to ring closure with the resultant formation of 1-ethylcytosine; small amounts of 1-ethyluracil are also produced. Heating of IIa and IIb produces 1-ethyluracil as the sole product. Spectroscopic properties were determined for each of these opened ring products, as well as for N-(N'-ethylcarbamoyl)-3-amino-2-methylacrylamidine (III) and N-(N'-ethylcarbamoyl)-3-amino-2-methylacrylamide (IV). Quantum yield measurements showed that Ia was formed with a phi of 1.6 x 10(-4) at pH 9.8, while phi for formation of IIa was 7.2 x 10(-4) at pH 11.5. A profile of the relative quantum yield for formation of Ia, determined as a function of pH, showed that the maximum quantum yield occurs at around pH 9.5; the analogous profile for IIa shows a maximum quantum yield at pH 11.3 and above. Acetone sensitization does not produce Ia in the Cyt-ethylamine system, which indicates that the known triplet state of Cyt is not involved in reactions leading to this opened ring product.
Cytosine↗
Ileal mucosal growth during intraluminal infusion of ethylamine or putrescine.
Either ethylamine or the diamine putrescine was infused at the rate of 1 mumol/h for 66 h into the ileal lumen of rats. Total mucosal RNA, DNA, and protein content was greater in amine-treated rats than in rats receiving 0.9% NaCl. Growth was greatest in the mucosa surrounding the tip of the infusion catheter but was also observed 9 cm proximal and distal to the catheter tip. Infusion of these amines induced the activity of the enzymes ornithine and S-adenosylmethionine decarboxylase. Ornithine decarboxylase activity was increased 2- and 6-fold and S-adenosylmethionine decarboxylase activity 10- and 5-fold by putrescine and ethylamine, respectively. Induction of the polyamine biosynthetic enzymes was not accompanied by increases in the tissue content of polyamines. Putrescine, spermidine, and spermine content of the ileal mucosa surrounding the catheter tip was the same in 0.9% NaCl-, ethylamine-, and putrescine-treated animals. Finally, ethylamine was without effect on serum gastrin concentration in these experiments. The results suggest that amines regulate mucosal growth and may do so by modulating the activity of the enzymes involved in the synthesis of the polyamines.
Adenosylmethionine Decarboxylase↗
Fine-tuning of copper(I)-dioxygen reactivity by 2-(2-pyridyl)ethylamine bidentate ligands.
Copper(I)-dioxygen reactivity has been examined using a series of 2-(2-pyridyl)ethylamine bidentate ligands (R1)Py1(R2,R3). The bidentate ligand with the methyl substituent on the pyridine nucleus (Me)Py1(Et,Bz) (N-benzyl-N-ethyl-2-(6-methylpyridin-2-yl)ethylamine) predominantly provided a (mu-eta(2):eta(2)-peroxo)dicopper(II) complex, while the bidentate ligand without the 6-methyl group (H)Py1(Et,Bz) (N-benzyl-N-ethyl-2-(2-pyridyl)ethylamine) afforded a bis(mu-oxo)dicopper(III) complex under the same experimental conditions. Both Cu(2)O(2) complexes gradually decompose, leading to oxidative N-dealkylation reaction of the benzyl group. Detailed kinetic analysis has revealed that the bis(mu-oxo)dicopper(III) complex is the common reactive intermediate in both cases and that O[bond]O bond homolysis of the peroxo complex is the rate-determining step in the former case with (Me)Py1(Et,Bz). On the other hand, the copper(I) complex supported by the bidentate ligand with the smallest N-alkyl group ((H)Py1(Me,Me), N,N-dimethyl-2-(2-pyridyl)ethylamine) reacts with molecular oxygen in a 3:1 ratio in acetone at a low temperature to give a mixed-valence trinuclear copper(II, II, III) complex with two mu(3)-oxo bridges, the UV-vis spectrum of which is very close to that of an active oxygen intermediate of lacase. Detailed spectroscopic analysis on the oxygenation reaction at different concentrations has indicated that a bis(mu-oxo)dicopper(III) complex is the precursor for the formation of trinuclear copper complex. In the reaction with 2,4-di-tert-butylphenol (DBP), the trinuclear copper(II, II, III) complex acts as a two-electron oxidant to produce an equimolar amount of the C[bond]C coupling dimer of DBP (3,5,3',5'-tetra-tert-butyl-biphenyl-2,2'-diol) and a bis(mu-hydroxo)dicopper(II) complex. Kinetic analysis has shown that the reaction consists of two distinct steps, where the first step involves a binding of DBP to the trinuclear complex to give a certain intermediate that further reacts with the second molecule of DBP to give another intermediate, from which the final products are released. Steric and/or electronic effects of the 6-methyl group and the N-alkyl substituents of the bidentate ligands on the copper(I)-dioxygen reactivity have been discussed.
Journal Article↗
Synthesis and pharmacological characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl derivatives as dopamine receptor ligands.
2-(4-Chloro-3-hydroxyphenyl)ethylamine (4) and some derivatives were synthesized as dopamine (DA) receptor ligands. Amine 4 retains the dopaminergic pharmacophore 2-(3-hydroxyphenyl)-ethylamine, and the chlorine atom replaces the "para" hydroxyl group of DA. The derivatives 18a-e were obtained by introducing on the nitrogen of amine 4 the n-propyl and 2-phenylethyl or 3-phenylpropyl groups which can be accommodated by the D-2 receptor lipophilic sites 3C and pi 3, respectively. The affinity and selectivity of these compounds for D-1 and D-2 subtypes was determined in radioligand competition assays for the DA receptors of rat striatum membranes using [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. The amine 4 shows about 7-fold lower affinity than DA for both sites and is not able to discriminate between the two subtypes of DA receptors. The introduction of two n-propyl groups (18a) on the nitrogen atom reduces by one-half and doubles the affinity for D-1 and D-2 binding sites, respectively. The substitution of an n-propyl group with different alkylphenyl groups, to give compounds 18b-e, increases the affinity for the D-2 subtype from 19-fold to 36-fold. These compounds have the same affinity at the D-2 site as the DA agonist N-n-propyl-N-(2-phenylethyl)-2-(3-hydroxyphenyl)-ethylamine (2a) and are about 20 times more selective than DA for this binding site. In the assay for D-2 receptor mediated inhibition of adenylate cyclase activity, all the tested compounds behaved as D-2 agonists; N-n-propyl-N-[2(4-hydroxyphenyl)ethyl]- (18d) and N-n-propyl-N-(2-phenyl-ethyl)-2-(4-chloro-3-hydroxyphenyl)ethylamine (18b) were more effective than DA or 2a. On the other hand, all compounds were less effective than DA in stimulation of adenylate cyclase activity in rat striatal homogenates, a kind of effect which is mediated by the D-1 subtype of DA receptors. These results suggest that the nitrogen substitution enhances the affinity and selectivity for the D-2 receptor. In the adenylate cyclase assay, the compounds behave as potent D-2 agonists.
Adenylyl Cyclases↗
Preparation and biological actions of N-2,2,2-trifluoroethyl-2-(3,4-dihydroxyphenyl)ethylamine.
N-2,2,2,-Trifluoroethyl-2-(3,4-dihydroxyphenyl)ethylamine was synthesized and compared to N-ethyl-2-(3,4-dihydroxyphenyl)-ethylamine and dopamine for activity on adenylate cyclase in the rat striatum. Both dopamine and N-ethyl-2-(3,4-dihydroxyphenyl)ethylamine stimulated adenylate cyclase activity in a dose-dependent fashion. The N-trifluoroethyldopamine analog at 1 x 10(-4) M induced a weak effect. The compounds were evaluated further by studying their relaxant effects in isolated rabbit renal and ear arteries. Both the N-ethyl- and N-trifluoroethyldopamine analogs produced a relaxant effect but demonstrated no selectivity for dopamine receptors.
Adenylyl Cyclase Inhibitors↗
Behavioural evidence for central D-2 dopamine receptor agonistic effect by some 2-(fluorohydroxyphenyl)ethylamines.
The IP injection of 2-(4-fluoro-3-hydroxyphenyl)ethylamines. (FDA 24), N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (FDA 27F) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3-hydroxyphenyl) ethylamine (FDA 40) into adult male rats induced the stretching and yawning (SY) syndrome, FDA 24 being the least active. Moreover, FDA 27F and FDA 40 potentiated penile erection (PE) with respect to controls. For both signs (PE and SY), FDA 40 was the most potent of the three compounds. These effects, which are considered typical signs of central D-2-dopamine (DA) receptor stimulation, were dose-related and significantly inhibited by pretreatment with the selective D-2 DA antagonist, sulpiride, but not by domperidone, which does not cross the hematoencephalic barrier. In previous binding studies, FDA 27F and FDA 40 showed high affinity and selectivity for D-2 DA receptors, while FDA 24 had a low affinity for both D-1 and D-2 DA receptors. The present data show that FDA 27F and FDA 40 cross the blood-brain barrier and exert an agonistic effect on the central D-2 DA receptors. These results also provide evidence of the value of PE and SY tests as sensitive tools for the study of DA-neurochemical mechanisms.
Animals↗
Synthesis and dopamine receptor affinities of 2-(4-fluoro-3- hydroxyphenyl)ethylamine and N-substituted derivatives.
The synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some N,N-dialkyl derivatives (27-30) starting from 4-fluoro-3-hydroxytoluene and their in vitro binding affinities for dopamine (DA) receptor are reported. The amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26-30 were evaluated for their affinity at D-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3- hydroxyphenyl)ethylamine (30) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-1 sites. The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor.
Animals↗
Structure-activity relationships of N-n-propyl-2-(4-fluoro-3-hydroxyphenyl)ethylamine derivatives as dopamine receptor ligands.
A series of N-n-propyl-2-(4-fluoro-3-hydroxyphenyl)ethylamine derivatives obtained by introducing on nitrogen atom a 2-phenylethyl moiety (with aromatic nucleus substituted at 3 or 4 position with fluorine, chlorine or hydroxy and methyl groups), as well as a 2-cyclohexylethyl or 3-phenylpropyl groups were synthesized. These substituents can interact with the D2 accessory binding site pi 3. The affinities of new compounds for D1 and D2 subtypes of dopamine (DA) receptor were measured in a test involving displacement of [3H]SCH 23390 and [3H]spiperone, respectively, from homogenates of rat striatum. The new derivatives are selective for D2 sites, and are more potent than the parent compound N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3-hydroxyphenyl)ethylamine 2a. The N-n-propyl-N-[2-(4-hydroxyphenyl)ethyl]-2-(4-fluoro-3-hydroxyphenyl) ethylamine (11f) is the most potent and selective member in the series. Other derivatives are less effective but are as potent as the D2 agonist RU 24213. The results indicate that the pi 3 site is a rather large lipophilic pocket which can accommodate not only aromatic nuclei, but also the cyclohexyl group.
Animals↗
Trace amines (ethylamine, octopamine, and tryptamine) stimulate inositol phospholipid hydrolysis in rat cerebral cortex slices.
Ethylamine, octopamine, tryptamine, and carbachol stimulate inositol phosphate accumulation in a dose-dependent way in rat cortical slices. Tyramine at 100 microM has no effect. The major inositol phosphate that is accumulated following stimulation is the monophosphate. The effect of carbachol is blocked by atropine but not by cyproheptadine, phenoxybenzamine, haloperidol or propranolol. None of the antagonists tried, including atropine, had an effect on the stimulation caused by ethylamine, octopamine or tryptamine.
Animals↗
Ethylamine in human urine.
The urinary excretion of ethylamine has been measured in 200 unrelated healthy volunteers (100 male, 100 female) who maintained their normal diet. The average daily output was 7.82+/-7.03 mg (mean+/-S.D.) (8.01+/-7.40 male; 7.64+/-6.67 female) with a range of values spreading from 0.22 to 35.27 mg. Dietary studies investigating 41 food substances did not highlight any major sources of this amine, except that drinking tea increased subsequent urinary ethylamine levels.
Adult↗
A new class of Gd-based DO3A-ethylamine-derived targeted contrast agents for MR and optical imaging.
Synthetic bifunctional probes based on [4,7-bis-carboxymethyl-10-(2-aminoethyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-acetic acid (DO3A-ethylamine) preloaded with gadolinium were prepared for applications in targeted magnetic resonance imaging (MRI) and optical imaging. A convenient route of synthesis is reported, which allowed conjugation of this probe with biomolecules for the preparation of model MR contrast agents for targeted imaging. The conjugated probes have the following interesting properties: GdDO3A-ethylamido-biotin (Gd-9) can be used for targeted imaging using an avidin-biotin system. The fluorescent probe GdDO3A-ethylthiourea-fluorescein (Gd-12) is a bimodal compound, which can be used for both MR and optical imaging. The precursors, DO3A-ethylamidopropyl-maleimide and DO3A-ethyl-isothiocyanate contain a highly reactive moiety, which can interact with free SH-terminals and N-terminals of biological molecules, respectively. In vitro MR relaxivity studies were performed at 300 MHz using different concentrations and chemical environments. MR relaxivity for ligand Gd-9 at pH 7.4, r1 was (3.32 +/- 0.03) s(-1) mM(-1) and r2 was (5.02 +/- 0.14) s(-1) mM(-1). For the mixture of Gd-9 with avidin, at pH 7.4, relaxivity increased linearly with the avidin concentration. A relaxivity enhancement of 45% for r1 and more than 400% for r2 with respect to the unbound biotinylated Gd3+ complex was found at a ratio of 4:1. MR relaxivity for ligand Gd-12, r1 was (5.36 +/- 0.05) s(-1) mM(-1) at pH 7.4. Fluorescence microscopy and spectroscopy of Gd-12-labeled 3T3 mouse fibroblasts showed a concentration-dependent intracellular uptake, accompanied by a slight dose-dependent increase in toxicity up to 150 microM. MR studies on labeled cells indicated a contrast enhancement in both T1- and T2-weighted images by the internalized compound, with the effect being more pronounced in T2-weighted images. Our results indicate that DO3A-ethylamine is a multipurpose precursor, from which various targeted contrast agents can be synthesized after a single-step conjugation with organic/bioorganic molecules.
Animals↗
Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: structural requirements and binding affinity at the sigma receptor.
By synthesizing and testing a part-structure, N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3), derived from our previously reported high affinity sigma receptor ligands (1S,2R)-(-)-N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1- pyrrolidinyl)cyclohexylamine [(-)-2] and (+)-2, we have identified a novel class of superpotent (subnanomolar affinity) sigma ligands specific for the sigma receptor labeled by [3H]-(+)-3-PPP. When 3 was tested for its capacity to displace [3H]-(+)-3-PPP from guinea pig brain membranes, it exhibited a Ki of 0.34 nM, which is better than either of its parent compounds (-)-2 (Ki = 1.3 nM) and (+)-2 (Ki = 6.0 nM). Other compounds related to 3 such as N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-homopiperidinyl)ethy lamine (19) exhibited Ki = 0.17 nM [( 3H]-(+)-3-PPP). The determinants for high sigma receptor affinity of 3 were examined by manipulation of this structure in a number of different ways. The high efficacy of these compounds for the sigma receptor, their relative chemical simplicity and ease of synthesis, and their high degree of selective identifies N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) and related compounds as a highly promising base for determination of the functional role of sigma receptors as well as the development of novel therapeutic agents.
Animals↗
[Synthesis and biological activity of substituted 2-(4-imidazolyl)ethylamines].
The synthesis of 2-(4-imidazolyl)ethylamines with hydrocarbon substituents on the heterocyclic ring or on the side-chain, from 2-acylbutyrrolactones (V) or from similar ester-type open structures (VII) is described in this paper. In particular, the results already obtained, show that the scheme given for the preparation of 2-(5-methyl-4-imidazolyl)ethylamines can be rendered general, by suitable variations correlated more with side-chain branching, than with the nature of the heterocyclic ring substituents. Synthetized imidazolyethylamines have been preliminarily tested for their properties towards H2 receptors and, secondly, towards H1 receptors.
Animals↗
Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase.
Lysyl oxidase initiates the covalent cross-linking of elastin and collagen, converting lysyl residues in these proteins to peptidyl aldehyde residues. The present study explored structural and electron withdrawing features required to generate mechanism-based inhibitors of this enzyme with antifibrotic potential. It was found that the electron withdrawing nitrile moiety of beta-aminopropionitrile (BAPN), a naturally occurring syncatalytic inhibitor of lysyl oxidase, can be replaced by chlorine, bromine, or the nitro function to yield 2-haloamines or nitroethylamine compounds which also act as mechanism-based irreversible inhibitors of this enzyme. BAPN and 2-bromo- and 2-chloroethylamine exhibit similar KI values of 6-10 microM. However, the enzyme becomes irreversibly inactivated significantly faster by either of the 2-haloamines than by BAPN. 2-Nitroethylamine has by far the poorest affinity for the enzyme and inactivates much more slowly than the other amines of this series, consistent with interference with optimal enzyme-inhibitor interactions by the anionic nitro group. Unlike BAPN, 2-bromoethylamine is processed to a detectable aldehyde product upon incubation with enzyme, showing a partition ratio of 1.2 mol of acetaldehyde formed per mol of 2-bromo-ethylamine which becomes covalently incorporated in the enzyme. The results are consistent with the processing of 2-bromo-ethylamine to an enzyme-ethyleneamine Schiff base subject to hydrolysis to acetaldehyde or to covalent attack at carbon 2 by an enzyme nucleophile. Thus, beta-haloamines represent a new series of suicide inhibitors of lysyl oxidase which can inactivate the enzyme faster than BAPN and hence may have antifibrotic potential.
Amino Acid Oxidoreductases↗
Synthesis and pharmacological properties of N-aroyl-beta-(1-indanyl)-ethylamines.
Six new N-acyl derivatives of beta-(1-indanyl)ethylamine were obtained. The most active of them, N-(m-chlorobenzoyl/-beta-1-indanyl)-ethylamine (compound 2), decreased the 5-HTP-induced head twitches in mice and the tryptamine-induced syndrome in rats, attenuated the quipazine-induced stimulation of the hindlimb flexor reflex in spinal rats, and reduced the immobility time in mice in the behavioral despair test. All these effects might be indicative of the antidepressive properties of compound 2.
Analgesics↗