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PubMed1994

[Interaction of formaldehyde with nucleic acids and their structural components in the presence of amines. V. Isotopic exchange of hydrogen 3H---1H at the C8 atom of dATP, adenosine, adenine, guanosine, and poly(A)].

It has been shown that the effect on [8-3H]dATP, [8-3H]A and [8-3H]poly(A) of the formaldehyde mixture with the primary aliphatic amine carrying an amino group at the chain terminus (glycine, its methyl and ethyl esters, tripeptide Gly-Gly-Gly, taurine, ethanolamine, methylamine, ethylamine), under conditions close to physiological ones (pH 5.5-9, 40-50 degrees), initiates a fast reaction of isotope H2 exchange: 3H-->1H at the C-8 atom of the adenine residue. Substitution of the primary amine for a secondary one decreases the rate of hydrogen exchange by more than two orders of magnitude. Under the effect of the formaldehyde mixture with Gly or Sar on guanosine or of the HCHO-Sar mixture on adenosine, the hydrogen exchange at the C-8 atom of the both nucleotides proceeds at the same rate. The mechanism of fast hydrogen exchange at the C-8 atom of 9-substituted adenines under conditions of the Mannich reaction via the N6,N7-cycloderivative (III) is discussed.

Adenine↗
PubMed1993

Electrophysiological effects of putative autoreceptor-selective dopamine agonists on A10 dopamine neurons.

The dopamine (DA) hypothesis of schizophrenia proposes hyperactivity of the mesocorticolimbic DA system, originating within the A10 DA cells of the ventral tegmental area (VTA), as a pathophysiological mechanism. Thus, reduction of activity in this system, including that produced by putative "autoreceptor-selective" DA agonists, may be of clinical utility. The present studies compared the ability of eight D2 DA receptor agonists to inhibit the firing of rat A10 DA neurons after i.v. administration. Both N-n-propyl-N-phenylethyl-p(3-hydorxyphenyl)ethylamine hydrochloride (RU 24213) and 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]- azepine dihydrochloride (B-HT 920) were potent, high-efficacy agonists which completely inhibited the firing of A10 DA cells. The putative autoreceptor-selective DA agonists 3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-(1)-butyl)-indole hydrochloride (EMD 23,448) and (+)-3-(3-hydroxy-phenyl)-N-n-propylpiperidine [(+)-3-PPP] were considerably weaker than RU 24213 and B-HT 920, but also exhibited "full" efficacy (i.e., they completely suppressed cell firing). The putative autoreceptor agonist preclamol [(-)-3-PPP] and its trans-fused congener (-)-HW 165 were weak partial agonists that failed to completely inhibit A10 DA cells. The new putative autoreceptor agonist N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,3]dimethylopropa namide (SDZ 208-911) was also a weak partial agonist that exhibited partial antagonist effects (reversed inhibition produced by the D2 agonist quinpirole), whereas its structural analog N-[(8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2-dimethylopropa namide (SDZ 208-912) was nearly inactive as an agonist, but was an effective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Microsomal N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene and the reactivity of N-hydroxy-N-methyl-4-aminoazobenzene.

The N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene (MAB) was catalyzed by hepatic microsomes in a reduced pyridine nucleotide- and oxygen-dependent reaction. The initial N-oxidation product, N-hydroxy-N-methyl-4-aminoazobenzene (N-HO-MAB), was readily oxidized to a second product that yielded N-hydroxy-4-aminoazobenzene upon subsequent acid treatment. The secondary N-oxidation product may be formed nonenzymatically and is presumed to be N-HO-MAB N-oxide or its dehydrated derivative, N-(p-phenylazophenyl)nitrone. Under the same conditions, MAB was also oxidatively N-dealkylated to 4-aminoazobenzene, which was N-oxidized to N-hydroxy-4-aminoazobenzene. Unlike the latter reactions, the microsomal N-oxidation of MAB was independent of cytochrome P-450, as shown by its lack of sensitivity to inhibition by 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine and its inability to utilize cumene hydroperoxide in place of reduced pyridine nucleotides and oxygen. The N-oxidation of MAB was also catalyzed by the purified microsomal flavoprotein mixed-function amine oxidase of Ziegler et al. The noncarcinogenic dye N-ethyl-4-aminoazobenzene was metabolized similarly to MAB. For male animals the hepatic levels of MAB N-oxidase activity were in the order: rat greater than hamster, guinea pig greater than mouse, rabbit. Little or no MAB N-oxidase activity was present in several extrahepatic rat tissues. N-HO-MAB, N-hydroxy-N-ethyl-4-aminoazobenzene, and N-hydroxy-4-aminoazobenzene catalyzed the aerobic oxidation of cysteine and glutathione. These hydroxylamines also bound covalently to proteins. The binding of N-HO-MAB with nucleic acids was only 3 to 6% that observed with serum albumin. Under anhydrous conditions the nitrone generated aerobically from N-HO-MAB reacted with carbon-carbon or carbon-nitrogen double bonds, or both, in fatty acids, retinol, purines, and pyrimidines to yield isoxazolidine and/or oxadiazolidine addition products. The nitrone from N-hydroxy-N-ethyl-4-aminoazobenzene was much less reactive under these conditions. Syntheses of N-HO-MAB and N-hydroxy-N-ethyl-4-aminoazobenzene are reported.

Aminobenzoates↗
PubMed1993

Cytochrome P450 2B isoenzymes are responsible for the pulmonary bioactivation and toxicity of butylated hydroxytoluene, O,O,S-trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl.

O,O,S-Trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl damage the type I pneumocytes of the alveolar epithelium in rats. Butylated hydroxytoluene causes similar damage in mice. The toxicity of these compounds is dependent on their bioactivation by the cytochrome P-450 (CYP) system. A range of compounds, that modifies the activity of specific CYP isoenzymes, has been used to establish those particular isoenzymes involved in bioactivation. Pulmonary toxicity was assessed by measurement of lung weight and changes in the activity of gamma-glutamyltranspeptidase and alkaline phosphatase in bronchoalveolar lavage fluid. O,O,S-Trimethylphosphorodithioate, bromophos, p-xylene and 2,4-dichloro-(6-phenyl-phenoxy)ethylamine all inhibited the dealkylation of pentoxyresorufin, an indicator of CYP2B1 activity, and also prevented pulmonary toxicity. There was a significant negative correlation between the level of pulmonary pentoxyresorufin dealkylation after pretreatment with O,O,S-trimethylphosphorodithioate and the severity of lung injury. This pretreatment also reduced the toxicity of butylated hydroxytoluene by a factor of 20 and methylcyclopentadienyl manganese tricarbonyl by a factor of 10. Modification of the activity of CYP1A1, CYP2E1 and CYP4B1 did not alter the toxicity of these compounds. These results indicate that pulmonary CYP2B1 is responsible for the bioactivation and toxicity of O,O,S-trimethylphosphorothioate and methylcyclopentadienyl manganese tricarbonyl in rats and the orthologous 2B isoenzyme in mice activates butylated hydroxytoluene.

Animals↗
PubMed1996

Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors.

We have shown previously that low doses of selective sigma (sigma)-receptor ligands potentiate the excitatory response of pyramidal neurons to NMDA in the CA3 region of the dorsal hippocampus in the rat. Because progesterone competitively displaces the binding of the ligand N-[3H]allyl-normetazocine (SKF-10,047), the present studies were undertaken to determine in vivo the effect of neuroactive steroids on NMDA-induced excitation of rat CA3 pyramidal neurons. Low doses of dehydroepiandrosterone (DHEA) potentiated the NMDA response selectively and dose-dependently. The effect of DHEA was reversed by the selective sigma antagonist N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl)-ethylamine monohydrochloride (NE-100) and by haloperidol, but not by spiperone. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by nonsteroidal sigma ligands. Neither pregnenolone nor pregnenolone sulfate had any effect on the NMDA response--nor did they antagonize the potentiation of the NMDA response induced by DHEA and by nonsteroidal sigma ligands. A pertussis toxin pretreatment, which inactivates Gi/o-proteins, abolished the potentiating effects of DHEA. Ovariectomy enhanced the potentiation of the NMDA response by the nonsteroidal sigma ligand di(2-tolyl)guanidine (DTG). There was a reciprocal occlusion of the effects of DHEA and DTG; DTG did not potentiate the NMDA response further after DHEA, and DHEA did not do so after DTG. These results suggest that some neuroactive steroids modulate the NMDA response via sigma receptors.

Animals↗
PubMed1996

Effect of insect-growth-disrupting amines and amides on Schistosoma mansoni in vitro.

A series of nonsteroidal alkylamines and alkylamides, which apparently inhibit phytosterol dealkylation in insects and free-living nematodes, as well as steps in the ecdysteroid biosynthetic pathway of insects, are also known to affect growth and development of animal-parasitic nematodes. The effect of these compounds on the motility, pairing, and viability of the trematode, Schistosoma mansoni, maintained in vitro was examined by incorporating the potential inhibitors into the medium employed for parasite culture. The alkylamines were more active than their amide counterparts, killing all parasites within 18 hr when tested at 25 parts per million. At lower concentrations, reductions in schistosome pairing and motility were observed. The functional group of the amine compounds influenced the schistosomicidal activity, with N-ethylamines being more effective than N,N-dimethylamines of identical carbon chain-length. Of all the compounds tested, N-ethyldodecanamine appeared to be the most promising schistosomicidal agent, killing all parasites within 22 hr at 10 parts per million and preventing parasite pairing at 3 parts per million.

Amides↗
PubMed1996

Enhancement of acetylcholine release by SA4503, a novel sigma 1 receptor agonist, in the rat brain.

We found that 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), a potent and selective sigma 1 receptor agonist, significantly enhanced the cerebral acetylcholine (ACh) release in the rat using in vivo brain microdialysis technique. Interestingly, the significant enhancement of ACh release elicited by SA4503 was observed in the rat frontal cortex and hippocampus, although the striatal ACh release was unchanged. This cortical ACh release was fully reversed by haloperidol, a prototype sigma receptor antagonist, or by N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride, a putative sigma 1 receptor antagonist. In addition, this enhanced ACh release by SA4503 was inhibited by tetrodotoxin, a Na+ channel blocker. However, tetrahydroaminoacridine, an acetylcholinesterase inhibitor, significantly increased the extracellular ACh level in the rat frontal cortex and weakly increased the hippocampal level. This compound also showed the significant increase of extracellular ACh level in the rat striatum. Moreover, tetrahydroaminoacridine markedly produced cholinomimetic side-effects, such as hypothermia, tremor, miosis and lacrimation. However, SA4503 did not produce these cholinomimetic side-effects. These findings suggest that SA4503 enhances the ACh release that is mediated through a novel mechanism, namely sigma 1 receptor subtype. Furthermore, SA4503 has regional differences in the enhancement of cerebral ACh release, and did not produce cholinomimetic side-effects. These profiles are different from tetrahydroaminoacridine.

Acetylcholine↗
PubMed1997

In vitro and in vivo characterization of a calcium modulator of the diphenylalkylamine type with selective coronary dilatory properties.

UNLABELLED: VUF 8929 (N-¿2-[bis(p-fluorophenyl)methoxy]ethyl¿-(2-phenyl)ethylamine maleate, CAS 140890-71-7) is a diphenylalkylamine derivative structurally related to prenylamine. The calcium antagonistic properties of this compound have been studied in in vitro and in vivo systems. VUF 8929 has affinity for the voltage-operated calcium channel. Its pKD for the displacement of [3H]nitrendipine bound to cerebral rat cortex is 6.27 (+/- 0.17). The compound influences the [3H]nitrendipine binding through an allosteric interaction with a site adjacent to the dihydropyridine binding site. Competitive experiments with the additional presence of the phenylalkylamine gallopamil showed that this allosteric site is a property common to diphenyl- and phenylalkylamines. It was further observed that VUF 8929 has a high affinity for calmodulin as it shows high potency in inhibiting the calmodulin mediated activation of PDE. The inhibition of K+ (IC50 0.5 mumol/l)- and noradrenaline (IC50 1.3 mumol/l)-induced contractions of rabbit aorta rings was in the same concentration range as found for the calmodulin inhibitory activity. In vitro platelet aggregation was also inhibited in the same concentration range when washed platelets were used. Thus calmodulin antagonism may contribute to the observed effects on aorta ring contractions and platelets aggregation. Platelet aggregation, however, in media in which albumin was added or in platelet rich plasma was not affected. It is assumed that due to the high lipophilicity, common to many diphenylalkylamines, VUF 8929 has a strong binding to plasma proteins. This may also explain why orally administered VUF 8929 did not affect the alpha 2-induced pressor response in pithed rats and the ex vivo collagen induced aggregation response. The haemodynamic profile in anaesthetized dogs showed that intravenous injected VUF 8929 reduced the workload of the heart while coronary blood flow increases at a dose of 0.3 mg/kg. Reversible occlusion of the coronary artery, which leads to S-T segment elevation and local venous acidosis, were reduced by VUF 8929 indicating that the compound has anti-ischaemic properties. IN CONCLUSION: VUF 8929 is a calcium antagonist which has anti-ischaemic properties, reduces the workload of the heart and increases coronary flow. Due to these properties VUF 8929 is a potential cardioprotective agent.

Adrenergic alpha-2 Receptor Agonists↗