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M Leven

Publications and source records attributed to M Leven.

14 recordsLinked to original sources
PubMed1988

4,4-Diphenylpiperidine derivates and their sila analogues. A comparative study of their interaction with neural receptor biding sites and synaptosomal monoamine uptake.

The potential anti-Parkinson drugs 1-R-4,4-diphenylpiperidines and 1-R-4,4-diphenyl-4-sila-piperidines (R = H, CH3, i-propyl and t-butyl) were evaluated for their neuroreceptor affinity with respect to their structure-activity relationship. In these compounds substitution of the central carbon at position 4 by a silicon leads to more lipophilic substances. While the binding of these compounds to dopamine, serotonin and gamma-aminobutyric acid/benzodiazepine receptors is relatively non-specific, the binding to the mu- and delta-subtypes of opiate receptors and to the 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine receptor binding site show probably pharmacologically relevant effects. In almost all cases the sila-compounds have a slightly higher receptor affinity than the corresponding carbon-compounds. The studies on the uptake sites for the biogenic amines noradrenaline, dopamine and serotonin, on the other hand, reveal some considerable differences between the carbon- and silicon-containing analogues. The 4,4-diphenyl-4-sila-piperidine has much stronger uptake inhibiting properties for noradrenaline and serotonin than the corresponding carbon compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines.

Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.

Animals↗
PubMed1987

Synthesis and neuroleptic activity of a series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzim idazolone derivatives.

A series of 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]benzimid azolones with various substituents in both aromatic rings have been synthesized and tested for neuroleptic activity (antiapomorphine effects and [3H]spiroperidol binding) as well as extrapyramidal effects (cataleptogenic effect). A strong dependence of activity on the 5-substituent in the benzimidazolone moiety could be demonstrated. Some compounds show a large split between the desired antiapomorphine and the undesired extrapyramidal effect. From these, 1-[1-(benzo-1,4-dioxan-2-ylmethyl)-4-piperidinyl]-5-chlor obenzimidazol-2-one hydrochloride (HR 723), 12, has been selected for further preclinical and toxicological profiling.

Animals↗
PubMed1984

Stereoselective inhibition of synaptosomal catecholamine uptake by nomifensine.

The effects of the two enantiomers of the antidepressant nomifensine on catecholamine uptake were investigated using rat brain synaptosomes. According to the results from in vitro and ex vivo/in vitro studies, the inhibitory activity on catecholamine uptake resides entirely in the (+)-form of nomifensine. Further studies comparing the antidepressant effects of the two enantiomers might help to clarify the validity of the catecholamine hypothesis of depression.

Absorption↗
PubMed1984

2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants.

The synthesis of various diastereoisomeric H4a,H5-cis,H4a,H9b-cis- and H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro -1H-indeno[1,2-b]pyridines is described, as well as the evaluation of their antidepressant potency. Elucidation of structure-activity relationships revealed the H4a,H5-trans compounds as being by far the more active of the two series of diastereoisomers. Pharmacological and biochemical data suggest that these compounds are potential antidepressants with central stimulating properties, which are characterized by strong norepinephrine and dopamine reuptake inhibition.

Animals↗
PubMed1982

The development of visual function in normal and neurologically abnormal preterm and fullterm infants.

Pattern preference for four different pairs of patterns, and visual acuity based on the ability to distinguish black and white stripes of different widths, were compared in neurologically normal and abnormal preterm infants at 36 and 40 weeks postmenstrual age and in normal and abnormal fullterm infants in the newborn period and again at four and six weeks of age. The study aimed to chart the maturation process of these visual functions in the neonatal period and to assess their predictive value in the neurologically abnormal infant. Part I of the study deals with the normal infant and Part II with the abnormal infant. In Part I, the maturation process for both visual functions in newborn preterm infants of increasing gestational age is compared with longitudinal assessment of postnatal maturation of these functions in preterm infants up to 40 weeks postmenstrual age. Up to 36 weeks postmenstrual age the functions were comparable in the maturing preterm infants and the newborn infants of comparable postmenstrual age, but at 40 weeks the preterm infants did less well than the fullterm newborn infants. In Part II, the abnormal fullterm infants demonstrated a significantly poorer pattern preference at the initial and subsequent examination. Visual acuity was significantly poorer at the initial examination but less marked at follow-up. The abnormal preterm infants showed poorer pattern preference and visual acuity at both 36 and 40 weeks postmenstrual age. Compared with neurologically abnormal infants without intraventricular haemorrhage (IVH), preterm infants with IVH showed no significant difference in pattern preference at 36 and 40 weeks, but a significant deficit in visual acuity.

Cerebral Hemorrhage↗
PubMed1979

Accumulation of radioiodinated tyrosine derivatives in the adrenal medulla and in melanomas.

Because tyrosine and dopa can be regarded as precursors of adrenomedullary hormones and melanin, radioiodinated derivatives of these compounds were tested for their accumulation in the adrenal medulla and in melanomas of various animal species. The highest level of accumulation in the adrenal medulla was attained in mice and rats with iodinated beta-hydroxy-alpha-methyltyramine, and in melanomas of mice with iodinated alpha-methyltyrosine. The results could not be reproduced to the same extent in other species.

Adrenal Medulla↗
PubMed1977

Pharmacological and biochemical studies with three metabolites of nomifensine.

Three major metabolites (M1, M2, M3) of nomifensine (8-amino-1,2,3,4-tetrahydro-2-methyl-4-phenyl-isoquinoline) are formed by hydroxylation and methoxylation of the phenyl ring. They were compared with nomifensine 1. in various psychopharmacological tests in vivo, carried out in mice after oral or i.p. treatment and 2. in neurochemical in vitro studies, measuring inhibition of noradrenaline (NA), dopamine (DA), and serotonin (5-HT) uptake in rat brain synaptosomes. M1 (4'-hydroxy-nomifensine) was the most active metabolite, while M2 and M3 had little or no effect in pharmacological tests. M1 reversed reserpine hypothermia in doses greater than 2.5 mg/kg, antagonized tetrabenazine catalepsy (ED50 68 mg/kg) and reversed oxotremorine hypothermia (ED50 33 mg/kg). In these tests nomifensine was also active, being about 3-10 times more potent than M1. In contrast to nomifensine M1 had also serotoninergic activity, potentiating both phenelzine-induced twitching (ED50 11 mg/kg) and the anticonvulsant effect of 5-hydroxytryptophan. Moreover, M1 prolonged the hexobarbital sleeping time in doses greater than 10 mg/kg, prevented nicotine-induced convulsions (ED50 58 mg/kg) and reduced the oxotremorine tremor (ED50 59 mg/kg). The LD50 of M1 was 1100 mg/kg orally. In vitro M1 was equipotent with nomifensine in inhibiting DA uptake (IC50 1.5 x 10(-7) M) and twice as active in inhibiting NA uptake (IC50 1.1 x 10(-8) M). In contrast to nomifensine M1 was also a potent inhibitor of 5-HT uptake (IC50 3.3 x 10(-7) M). M2 and M3 were less active than M1 in all experiments.

Animals↗
PubMed1977

Studies on brain metabolism of biogenic amines.

1. In vitro models (synaptosones, electrically stimulated brain slices and monoamine oxidase (MAO) preparations have been used to identify the sites of action of nomifensine on brain monoamine metabolism. 2. Nomifensine potentiates neurotransmission in noradrenergic and dopaminergic synapses by blocking catecholamine uptake. 3. Nomifensine does not inhibit MAO and does not enhance the release of biogenic amines. 4. Studies on electrically stimulated brain slices suggest that nomifensine does not directly stimulate dopamine (DA) nor noradrenaline (NA) receptor sites. 5. 5-Hydroxytryptamine (5-HT) uptake is not inhibited at "therapeutic" concentrations of nomifensine. 6. Nomifensine differs from the tricyclic antidepressants by virtue of its effect on the dopaminergic system.

Animals↗