Pieter Tepper
University of Groningen
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Featured researches published by Pieter Tepper.
European Journal of Pharmacology | 1984
M Beaulieu; Y Itoh; Pieter Tepper; As Horn; J.W. Kebabian
Mono- and di-N-substituted 2-amino-5-hydroxytetralins stimulate the D-2 dopamine receptor, 2-(N-n-propyl-N-phenylethylamino)-5-hydroxytetralin being the most potent D-2 agonist encountered to date. In contrast, 2-amino-5-hydroxytetralins only marginally stimulate the D-1 receptor; however, 2-(di-N-n-propylamino)-5, 6-dihydroxytetralin is equipotent with dopamine as a D-1 agonist. The results are discussed within the context of the two dopamine receptor hypothesis.
European Journal of Pharmacology | 1986
Jan Van der Weide; Jan de Vries; Pieter Tepper; Alan S. Horn
A series of new dopamine (DA) receptor agonists, of the 2-aminotetralin group, i.e. N-0434, N-0437 and N-0734 were investigated in both in vivo and in vitro pharmacological test systems. In vivo, the reversal of the gamma-butyrolactone-induced increase in rat central DOPA biosynthesis rate was taken as a measure of presynaptic activity. In addition, the homovanillic acid (HVA) decrease, after intraperitoneal and after oral administration of the drugs was also taken as a measure of presynaptic activity. Postsynaptic activity was measured in two behavioural models, i.e. reserpine reversal and stereotypy induction. The effects of these drugs on noradrenaline and dopamine turnover (alpha-MpT method) were studied in addition. The displacement of [3H]N,N-dipropyl-5,6-dihydroxy-2-aminotetralin [( 3H]DP-5,6-ADTN) binding to rat striatal homogenates was studied in vitro. The results indicate that all three compounds are potent and selective DA agonists that lack significant alpha 2 activity. Because of its long duration of action and high oral activity, N-0437 seems to be a most promising candidate for further evaluation for possible therapeutic use.
European Journal of Pharmacology | 1988
Jan Van der Weide; Maartje E.C. Tendijck; Pieter Tepper; Jan de Vries; Margarita L. Dubocovich; Alan S. Horn
The (+) and (-) enantiomers of the substituted 2-aminotetralin, N-0437 were evaluated in vivo for their dopaminergic activity, using biochemical as well as behavioural models. In presynaptic models, i.e. antagonism of gamma-butyrolactone-induced dihydroxyphenylalanine elevations and the induction of hypomotility, both enantiomers exhibited a similar high degree of potency. Following postsynaptic stimulation, (-)N-0437 was able to induce stereotypy in rats in a dose-dependent manner. Moreover this compound was able to produce rotation in 6-hydroxy-dopamine-lesioned rats. In contrast, at the doses tested (i.e. 1 and 10 mumol/kg, i.p.), (+)N-0437 displayed virtually no activity at all in either of these postsynaptic models. From in vitro evoked release studies of [3H]acetylcholine it became clear that (-)N-0437 is a postsynaptic dopamine agonist, while (+)N-0437 is a weak antagonist at these receptors. Taken together, the results indicate that (-)N-0437 is very selective for the stimulation of postsynaptic dopamine receptors, while (+)N-0437 stimulates presynaptic dopamine receptors and blocks postsynaptic receptors. These properties make (+)- and (-)N-0437 very promising candidates for psychotherapeutic use.
European Journal of Pharmacology | 1989
Löschmann Pa; Chong Pn; Masahiro Nomoto; Pieter Tepper; As Horn; Peter Jenner; C. D. Marsden
The selective dopamine D-2 receptor agonist N-0437 produced a rapid and dose-dependent reversal of motor deficits lasting 90-120 min following i.p. or oral administration of the racemate to MPTP-treated common marmosets. In contrast, topical application of (+/-)-, (+)- or (-)-N-0437 to the skin of MPTP-treated animals did not alter locomotor activity in the initial 4 h although other motor disabilities were reduced. However, 24 h following application of the racemate or the (-) enantiomer both locomotor activity and the other motor deficits induced by MPTP were improved. The increase in locomotor activity returned to basal values by 48-52 h following application of the racemate to the skin and by 72-76 h following administration of (-)-N-0437; the other motor deficits induced by MPTP were reduced for up to 72-76 h by both (+/-)- and (-)-N-0437. Application to skin of the (+) enantiomer produced no behavioural improvement or stimulation of locomotor activity. Transdermal administration of the active enantiomer of N-0437 may be of value in producing a prolonged reversal of parkinsonian motor deficits in man.
Pharmacy World & Science | 1985
As Horn; Pieter Tepper; J Vanderweide; M Watanabe; D Grigoriadis; P Seeman
The synthesis of a new, potent and selective D2 dopamine receptor agonist, N-0437, of the 2-aminotetralin group is described. The results of a radioreceptor binding assay using a homogenate of porcine anterior pituitary as a tissue source for D2 dopamine receptors and3H-spiperone as radioligand demonstrate that this compound is one of the most potent compounds so far evaluated in this test system.
European Journal of Pharmacology | 1987
J Vanderweide; Jb Devries; Pieter Tepper; As Horn
N-0437, a non-catecholic aminotetralin has recently been described as a very potent and selective dopamine D-2 agonist. In this study the in vitro binding of [3H]N-0437 (specific activity 80.6 Ci/mmol) to calf caudate membranes is described. It was found that [3H]N-0437 binds with a high affinity (KD = 0.17 nM) and a low proportion of non-specific binding. Moreover the binding was saturable with a high number of binding sites (Bmax = 703 +/- 28 fmol/mg protein) and reversible (dissociation half-time = 68 min). Pharmacological analysis of [3H]N-0437 binding showed that it was selective for dopamine receptors and that it was also stereoselective for D-2 receptors. Non-dopaminergic drugs were without exception very poor displacers. Taken together the results suggest that [3H]N-0437 labels dopamine D-2 receptors with a high selectivity in the calf brain, and thus, that it should be a useful tool in studies of central dopamine receptors.
European Journal of Pharmacology | 1988
J Vanderweide; Jb Devries; Pieter Tepper; Dn Krause; Ml Dubocovich; As Horn
The selectivity of the potent dopamine D-2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was examined in a series of in vivo and in vitro pharmacological models. In radioligand binding assays, N-0437 showed high potency (Ki = 0.69 nM) and selectivity for D-2 receptors as compared to its potency and selectivity at various other neuronal receptors (Ki in nM): D-1 (678) dopamine, alpha 1-(534) and alpha 2-(195) adrenoceptor, S1-(6940) and S2-(5900) serotonin and muscarine (2660). Very low activity (Ki greater than 10(-5) M) was seen at the beta-adrenoceptor, A1-adenosine, GABAA and benzodiazepine receptors. Furthermore, N-0437 inhibited the calcium-dependent release of [3H]dopamine (IC50: 4 nM) and [3H]acetylcholine (IC50: 6.3 nM) from rabbit striatal slices in the nanomolar range. These effects of N-0437 were mediated through activation of D-2 dopamine autoreceptors and D-2 dopamine heteroreceptors, respectively. Presynaptic dopaminergic activity in vivo was measurable as an inhibition of the locomotor activity of mice, and in this model N-0437 was more effective than apomorphine. Moreover, the effect of N-0437 could be antagonized by sulpiride but not by yohimbine. N-0437 was equipotent with apomorphine in inducing circling behaviour in 6-OHDA-lesioned rats. N-0437 had almost no serotonergic activity in vivo. The results show that N-0437 is a selective dopamine D-2 agonist, and thus, that it is a new ligand of choice for studies on the D-2 receptor.
European Journal of Pharmacology | 1984
Jc Vanoene; Jb Devries; Durk Dijkstra; Rjw Renkema; Pieter Tepper; As Horn
The potencies of a number of 2-aminotetralin derivatives as centrally acting dopamine (DA) receptor agonists were investigated using the reversal of the gamma-butyrolactone-induced increase in rat central DA biosynthesis rate as a measure of potency at DA autoreceptors and the reversal of the reserpine-induced immobility of mice as a measure of postsynaptic DA receptor stimulating potency. The results indicated that the compounds fell into two separate groups depending on their effectiveness in the postsynaptic test model. High postsynaptic effectiveness was achieved with compounds bearing a hydroxyl group at the 5 position of the aminotetralin structure, whereas aminotetralins lacking this substitution pattern were found to possess high DA autoreceptor selectivity. The observed dichotomy of DA agonists is discussed in relation to the possible involvement of multiple DA receptors and alpha-adrenoceptors.
European Journal of Pharmacology | 1989
W Timmerman; Ben H.C. Westerink; Jb Devries; Pieter Tepper; As Horn
An intracerebral dialysis method was used to test both enantiomers of the very potent and selective dopamine (DA) D-2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin, N-0437, for their actions on DA receptors in the striatum of the rat. (-)N-0437 induced a 60% decrease in DA release, which was independent of the presence or absence of a kainic acid lesion placed unilaterally in the striatum. Stereotyped behaviour was apparent following administration of the (-) enantiomer. Thus, (-)N-0437 displayed an agonistic action on both pre- and postsynaptic D-2 receptors. (+)N-0437 did not induce any effect in the release model after peripheral administration nor did it induce any form of stereotypy. A comparison between the effects of (-)N-0437 after oral (10 mumol/kg) and transdermal (10 mumol/kg) administration showed the advantages of the latter mode of administration. Transdermal application induced a much longer duration of action of the drug (13 h) in comparison with the oral mode (5 h). Thus, transdermal administration may be a very useful method of drug application for therapeutic use.
Chemistry: A European Journal | 2013
Edzard M. Geertsema; Yufeng Miao; Pieter Tepper; Pim de Haan; Ellen Zandvoort; Gerrit J. Poelarends
Call me Michaelase: The enzyme 4-oxalocrotonate tautomerase (4-OT) promiscuously catalyzes the Michael-type addition of acetaldehyde to a collection of aromatic and aliphatic nitroolefins with high stereoselectivity producing precursors of γ-aminobutyric acid (GABA) analogues.