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A S Horn

Publications and source records attributed to A S Horn.

At least 19 recordsLinked to original sources
PubMed1991

Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437.

Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxy-N-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured. The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors. Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Impact of structural differences on the in vitro glucuronidation kinetics of potentially dopaminergic hydroxy-2-aminotetralins and naphthoxazines using rat and human liver microsomes.

The in vitro glucuronidation of seven monohydroxy-2-aminotetralins and two naphthoxazines has been determined using human and rat liver microsomes. All these compounds stimulate the D2 dopamine receptor. The influence of the position of the phenolic hydroxyl group was studied with rat microsomes in monohydroxy-2-(N,N-dipropylamino)-tretralins. The highest activity and intrinsic clearance was found for 7-OH-DPAT, but the latter values for 5-OH-DPAT and 6-OH-DPAT were much lower by a factor of 9 and 30, respectively. The 8-OH-isomer was not glucuronidated at all. Substitution of a propyl side chain by a thienylethyl-, or phenylethyl side chain, in 5-hydroxy-DPAT, or in (+)-4-propyl-9-hydroxyhexahydronaphthoxazine (PHNO, N-0500), showed a large increase of the UDPGT affinity and intrinsic clearance especially for N-0437. It also resulted for N-0437 in a much higher affinity towards the dopaminergic D2 receptor. Although the glucuronidation activity of human microsomes was found to be considerably lower than that of rat microsomes, the latter phenomenon was clearly visible with human microsomes as well. These findings may have serious implications for the ability of these drugs to adequately reach the brain.

Animals↗
PubMed1991

Orally active carbamate prodrugs of the selective dopamine agonist N-0437: in-vivo activities in the 6-OHDA turning model and in-vitro activities.

The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37 degrees C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors.

Administration, Oral↗
PubMed1990

The effect of acetylcholinesterase inhibition on the release of acetylcholine from the striatum in vivo: interaction with autoreceptor responses.

The release of acetylcholine from the rat striatum is under inhibitory control of muscarinic autoreceptors. Since in vivo release studies are generally performed in the presence of an acetylcholinesterase inhibitor, modifications of responses to muscarinic receptor agonists and antagonists may be expected. In this study we show that the addition of 0.1 microM neostigmine bromide to the perfusion Ringer in a dialysis experiment attenuates the responses obtained by infusion of 100 microM oxotremorine and potentiates the effect of infusion of 1 microM atropine. Furthermore it is shown that under physiological conditions the muscarinic autoreceptors are not fully occupied, since infusion of 1 microM atropine did not affect the release of acetylcholine when no acetylcholinesterase inhibitor was added to the perfusion Ringer.

Acetylcholine↗
PubMed1990

The potential antipsychotic activity of the partial dopamine receptor agonist (+)N-0437.

The (+) enantiomer of the very potent and selective dopamine D-2 agonist, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437), displays partial agonistic activity at dopamine D-2 receptors. In this study (+)N-0437 was investigated for its antagonistic activity at postsynaptic DA receptors in four behavioural tests which are commonly used to evaluate potential neuroleptic activity, i.e. d-amphetamine-induced stereotypy, passive avoidance responding, intracranial self-stimulation behaviour, and catalepsy. (+)N-0437 (25-50 mumol/kg) was active in the first three models, but did not cause catalepsy. Haloperidol, which was used as a reference compound for classical DA antagonists, showed clear activity in all four models at low doses (0.5-1.0 mumol/kg). (-)N-0437, a full D-2 agonist, displayed no activity in these behavioural models. These results suggest that (+)N-0437 could be used to examine the hypothesis that the use of partial agonists could provide a new treatment for schizophrenia.

Animals↗
PubMed1990

An M3-like muscarinic autoreceptor regulates the in vivo release of acetylcholine in rat striatum.

Selective muscarinic antagonists were used in an attempt to characterize the muscarinic autoreceptor modulating the release of acetylcholine in the striatum of the rat. In vivo microdialysis was applied to infuse atropine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine), pirenzepine or AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro[2,3-b][1,4]benzodiazepine-6-one), leading to a dose-dependent increase in the overflow of acetylcholine, the order of potency being: atropine greater than 4-DAMP greater than pirenzepine greater than AF-DX 116. We conclude from these data that the muscarinic receptor modulating release in the striatum is of the M3 type.

Acetylcholine↗
PubMed1990

Partial purification of the 5-hydroxytryptamine-reuptake system from human blood platelets using a citalopram-derived affinity resin [corrected].

This paper describes a procedure for the synthesis and application of a citalopram-derived affinity resin in purifying the 5HT-reuptake system from human blood platelets. A two-step scheme has been developed for partial purification, based on wheat germ agglutinin-lectin (WGA) affinity and citalopram affinity chromatographies. Upon solubilization of the carrier with 1% digitonin, a 50-70-fold increase in specific [3H]imipramine binding activity with a 70% recovery could be accomplished through WGA-lectin chromatography. The WGA pool was then subjected to affinity chromatography on citalopram-agarose. At least 90% of the binding capacity adsorbed to the column. Specific elution using 10 microM citalopram resulted in a 22% recovery of binding activity. A 10,000-fold overall purification was obtained by using this two-step procedure. Analysis of the fractions on SDS-PAGE after 125I labeling revealed specific elution of 78- and 55-kDa proteins concomitant with the appearance of [3H]imipramine binding activity. The pharmacological profile of the partially purified reuptake system correlated well with that derived from the crude membrane-bound reuptake system, suggesting a copurification of the 5HT binding activity and [3H]imipramine binding activity.

5-Hydroxytryptophan↗
PubMed1990

Improvement of the oral bioavailability of the selective dopamine agonist N-0437 in rats: the in vitro and in vivo activity of eight ester prodrugs.

The potent and selective D2-agonist N-0437 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin undergoes considerable first-pass metabolism due to glucuronidation of the phenolic group after oral administration. In an attempt to improve the bioavailability, eight ester prodrugs of N-0437 were synthesized, i.e. the acetyl, isobutyryl, pivaloyl, benzoyl, 2-methylbenzoyl, 2-methoxybenzoyl, 2,4-dimethylbenzoyl and 2-aminobenzoyl analogues. To examine the hydrolysis rates of these compounds in vitro studies were performed in rat serum. The prodrugs showed a very diverse pattern of hydrolysis rates. The in vivo activities were determined by testing the prodrugs in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used to measure the activity of the compounds. By calculating the area under the curve (AUC), of the time-effect curves of the prodrugs, a significantly improved duration of action was found for those prodrugs which have a slow in vitro hydrolysis rate. However no significant differences in total activity of these slowly hydrolysing prodrugs compared with N-0437 could be demonstrated, although the 2-aminobenzoyl and the 2,4-dimethylbenzoyl derivatives show interesting behavioural profiles. In contrast the isobutyryl ester, a prodrug with a relatively rapid hydrolysis rate, gave an improvement of turning behaviour over the whole time course in comparison with N-0437.

Animals↗
PubMed1990

Transdermal administration of the dopamine agonist N-0437 and seven ester prodrugs: comparison with oral administration in the 6-OHDA turning model.

The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i.e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-amino-phenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues. In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl- and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application.

Administration, Cutaneous↗
PubMed1990

Ocular and systemic disposition of the dopamine agonist N-0437 in monkeys after ocular administration.

The ocular and systemic disposition of the new dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was investigated in conscious monkeys after ocular administration of 0.56 mg N-0437. HCl (corresponding to 0.50 mg free base), containing 200 microCi [3H]N-0437, into the right eye. After killing the animal, the eyes were removed and several eye tissues were dissected and assessed for their content of radioactivity. In the treated eye, the iris contained by far the highest concentration of radioactivity, while in the untreated eye the lower conjunctiva, the iris the ciliary body and the choroid possessed the highest levels of radioactivity. In all dissected eye tissues, a substantially higher concentration of radioactivity was established for the treated eye compared to the untreated eye, except for the vitreous in which for both eyes about an equal concentration was measured. This result suggests the presence of a systemic transport, which was confirmed by the occurrence of bradycardia, starting immediately after ocular application of the drug and lasting for about 1.5 hr. As the total amount of radioactivity in both eyes 7 hr after ocular dosing is very low (0.3-0.5% of the dose), one can conclude that N-0437 is almost completely taken up into the general circulation. The radioactive measurements of bile and urine samples collected up to 7 hr after administration revealed that the elimination of N-0437 and its metabolites is very fast, with the urinary excretion (35% of the dose) slightly higher than to the biliary one (31% of the dose).

Animals↗
PubMed1990

The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration. I. Disposition and metabolic profiling.

1. The disposition and metabolic profiling of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin(I), a dopamine agonist, were studied in anaesthetized rats after i.v. administration and in non-anaesthetized rats after i.v. and oral dosing. No major differences due to narcosis were observed. 2. Independent of dosing route or anaesthetic, clearance of I was rapid. Bile was the main route of excretion, accounting for 88% dose, compared with 9% in urine. 3. Drug metabolic profiling revealed that I is almost completely metabolized before elimination; less than 0.5% total radioactivity in bile and urine was due to parent compound. 4. The biliary metabolic profiles after i.v. and oral administration were similar. One major metabolite was detected, accounting for 50% (i.v.) or 65% (oral) dose. The major biliary metabolite was identified as the glucuronide of I. 5. Urinary metabolic profiles were quantitatively different from those of bile. After i.v. administration one major metabolite was detected in urine, but this was not the major biliary metabolite. After oral administration, the major urine metabolite was the same as the major biliary metabolite. These differences can be explained by first-pass gastro-intestinal metabolism.

Administration, Oral↗
PubMed1990

The metabolic fate of the dopamine agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin in rats after intravenous and oral administration. II. Isolation and identification of metabolites.

1. The in vivo metabolic pathways of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (I) in rats have been established, using in vitro metabolism as a complementary technique. 2. All identified metabolites were conjugates. Glucuronidation at the phenolic group yields the major metabolite, accounting for 50% (i.v.) or 65% (oral) of the dose. The corresponding sulphate conjugate of I is virtually absent (less than 0.2% dose). 3. Hydroxylation of I, at the ortho position to the phenolic hydroxy group, yields 6-hydroxy-I (II), accounting for about 13% (i.v.) or 9% (oral) dose. This catechol is excreted, as a glucuronide, almost exclusively into the bile. Both the 5- and the 6-glucuronide of II were detected in about equal amounts. 4. Metabolism of I in vitro showed that under oxidative conditions, depropylation of I occurred. Conjugation of 3H-I in the presence of UDPGA or PAPS, was successful in yielding the glucuronide and sulphate conjugates.

Administration, Oral↗
PubMed1989

The effects of the enantiomers of the dopamine agonist N-0437 on food consumption and yawning behaviour in rats.

The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their effects on palatable food consumption and yawning behaviour in rats. (-)-N-0437 (1.0 and 5.0 mumols/kg). This confirms the agonistic action of (-)-N-0437 on postsynaptic receptors as food consumption is considered to be related to stimulation of postsynaptic DA receptors. Yawning behaviour was stimulated by (-)-N-0437 (0.5 mumol/kg) and could be antagonized by the autoreceptor-selective antagonist (+)-UH 232 (25 mumols/kg), which suggests an agonistic action on DA autorecptors. (+)-N-0437 (5.0 and 10.0 mumols/kg) also reduced food consumption and the effect could be antagonized by YM 09151-2 (0.03 mumol/kg). The weaker effect of (+)-N-0437 on food intake in comparison to that induced by (-)-N-0437 can be explained if it assumed that (+)-N-0437 is a partial agonist. (+)-N-0437 did not induce yawning behaviour in rats, suggesting that autoreceptors mediating the release of DA may be involved in stimulating yawning by DA agonists.

Animals↗
PubMed1989

Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437.

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.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

The enantiomers of the dopamine agonist N-0437: in vivo and in vitro effects on the release of striatal dopamine.

The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their pharmacological actions on DA D-2 autoreceptors in vivo, by measuring DA release by microdialysis during local administration of both drugs and in vitro, by measuring their effects on the electrically stimulated release of [3H]DA from striatal slices. In both experimental situations (-)-N-0437, at low doses, acted as an agonist on receptors controlling DA release. However, in vivo at a concentration of 10 microM (-)-N-0437 induced a short-lasting increase in DA release and in vitro the inhibitory effect of (-)-N-0437 was significantly less pronounced at higher concentrations (1-10 microM). (+)-N-0437 (0.1-10 microM) showed an antagonistic action both in vivo and in vitro. Following inhibition of the neuronal impulse flow with tetrodotoxin, (+)-N-0437 failed to increase DA release suggesting the effect of this enantiomer is not associated with an amphetamine-like action on the nerve terminal. The use of the DA re-uptake inhibitor GBR 12909 confirmed the antagonism of (+)-N-0437 towards DA receptors. Since it is known that (+)-N-0437 acts as an agonist on DA D-2 autoreceptors controlling the synthesis of DA, these results provide additional evidence for the existence of distinct DA D-2 autoreceptor populations involved in the release and synthesis of DA. The differential actions of (-)- and (+)-N-0437 gave rise to mutual antagonism of the actions of the enantiomers both in vivo and in vitro, thus providing a strong argument for using the enantiomers instead of the racemate in clinical situations.

Animals↗