Selective Dopamine Autoreceptor Agonist Research Articles

ChemInform Abstract: Synthesis and Stereochemistry of Oxazolo(4′,5′:1,2)benz(5,4,3‐c,d) indole Derivatives as Intermediates on the Way to a Selective Dopamine Autoreceptor Agonist.

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Roxindole, a potential antidepressant I. Effect on the dopamine system

Roxindole (EMD 49980, 5-hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl(1))-butyl(1)]-indole mesylate), a selective dopamine autoreceptor agonist and a potential antipsychotic drug, shows a clinical antidepressant efficacy. The present paper examined the neuropharmacological profile of roxindole in rats (male Wistar) and mice (male Albino Swiss) in respect of its influence on dopamine system. Used in low doses, roxindole decreased the locomotor activity, but in higher ones it did not induce a locomotor hyperactivity or stereotypy. It antagonized the amphetamine-induced hyperlocomotion, the amphetamine- or apomorphine-induced stereotypy, apomorphine climbing behaviour and reserpine-induced akinesia. The quinpirole-induced hyperlocomotion was inhibited by roxindole. When given alone, the drug in question, did not induce the catalepsy, but antagonized the catalepsy induced by haloperidol, spiperone and fluphenazine. The immobility time in the forced swimming test was reduced. Like typical antidepressants, roxindole given repeatedly (twice daily, 14 days) increased the hyperlocomotion induced by D-amphetamine. The results described above indicate that roxindole may have an antidepressant and antiparkinsonian activity and should be devoid of extrapyramidal side-effects.

Synthesis and stereochemistry of oxazolo[4′,5′:1,2]benz[5,4,3‐c, d]‐indole derivatives as intermediates on the way to a selective dopamine autoreceptor agonist

AbstractAn expedient and practical variant of the synthesis of the selective dopamine autoreceptor agonist 5 from the benzindolone 1 is described. The reaction sequence includes a two‐fold epimerization at the α‐position of the lactam function. The structure of the intermediate 9a was confirmed by X‐ray structure analysis.

Dopamine autoreceptor agonists in the treatment of schizophrenic disorders

1. Synthesis and release of dopamine as well as firing rates of dopaminergic neurons are controlled by stimulation of autoreceptors via a negative feedback regulation, investigations on therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia have yielded inconsistent results. 2. With respect to the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in positive schizophrenic symptomatology in order to reduce the postulated excess of central dopaminergic activity. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of psychopathological symptoms. 3. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from open clinical trials suggests that dopamine autoreceptor agonists may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia and avolition.

Dopamine autoreceptor agonists in the treatment of schizophrenia and major depression.

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.

The dopamine autoreceptor agonist, (±)- Trans-1,3,4,4a5, 10b-hexahydro-4-propyl-2h [1]benzopyrano [3,4-b] pyridin-9-ol hydrochloride (CGS 15855A), modulates striatal dopamine metabolism and prolactin release

The effects of apomorphine and the putative dopamine autoreceptor agonist, CGS 15855A, were evaluated in several functional assays that are modulated by pre- or post-synaptic D 2 receptors. These included release of prolactin in vivo and in vitro from cultured lactotrophs; levels of dihydroxyphenylacetic acid (DOPAC) in the striatum; levels of acetylcholine (ACh); in the striatum and concentrations of cyclic guanosine monophosphate (cyclic GMP) in the cerebellum. The secretion of prolactin was inhibited by CGS 15855A in vitro and in vivo and which also decreased the levels of DOPAC in the striatum at doses 5–25 times less than those required to increase ACh in the striatum and levels of cGMP in the cerebellum. In contrast, apomorphine possessed a dose-ratio between 1.5 and 8.6 for these assay systems. These data suggest that CGS 15855A is a selective dopamine autoreceptor agonist which preferentially stimulates D 2 receptors on lactotrophs and dopaminergic neurons as compared to D 2 receptors on cholinergic interneurons in the striatum.

Imidazole and yohimbine antagonize hypomotility, penile erection, stretching and yawning induced in rats by BHT 920, a selective dopamine autoreceptor agonist

When the azepine derivative BHT 920, a putative agonist at dopamine autoreceptors, was injected i.p. into adult male rats at 100 μg/kg, it induced numerous penile erections, stretching and yawning and sedation, all considered typical signs of central DA autoreceptor stimulation, but did not elicit stereotyped behaviour. Imidazole (37.5–150 mg/kg i.p.) and the α2 antagonist yohimbine (0.5–1 mg/kg i.p.) both antagonized the behavioural effects of BHT 920. In the light of the proposed selective action of the drugs used, the possible involvement of specific receptors for the modulation of these forms of behaviour, as well the possible relevance of the data presented, are briefly discussed.

Dopamine autoreceptor stimulation increases protein carboxyl methylation in striatal slices.

We have investigated the possibility that protein carboxyl methylation is involved in coupling dopamine autoreceptor stimulation to intracellular events such as inhibition of dopamine synthesis or release. The dopamine agonists apomorphine and TL-99 were found to stimulate methyl ester formation in striatal slices preloaded with [3H]methionine. The stimulatory effects of apomorphine were dose-dependent, were not due to changes in [3H]methionine uptake or S-[3H]-adenosylmethionine formation, and were blocked by the stereospecific dopamine antagonist (+)-butaclamol. Stimulation of methyl ester formation by dopamine agonists is readily observed only when slices are prepared from rats pretreated with reserpine to deplete endogenous brain catecholamines. This suggests that in slices prepared from normal rats endogenous dopamine (DA) released during slice preparation and incubation masks the effects produced by exogenously administered dopamine agonists on protein carboxyl methylase (PCM) activity. Additional experiments suggested that the effects of apomorphine were mediated via an interaction with DA autoreceptors rather than with postsynaptic DA receptors. Destruction of monoamine neurons and their associated autoreceptors by injecting 6-hydroxydopamine into the area of the medial forebrain bundle abolished the stimulatory effects of apomorphine on methyl ester formation in striatal slices. Furthermore the putative selective DA autoreceptor agonist EMD 23 448 was also found to stimulate methyl ester formation in striatal slices. These findings, discussed in terms of calcium-dependent functions, support the hypothesis that PCM may be a key component in the biochemical transduction of DA autoreceptor stimulation.

The effectiveness of yohimbine in blocking rat central dopamine autoreceptors in vivo

The influence of various alpha-adrenoceptor antagonists (10 mg/kg i.p.) upon the rate of turnover of dopamine (DA) in the rat brain was investigated. Taking the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as a measure of the rate of DA turnover, it was found that prazosin and phenoxybenzamine decreased, whereas piperoxane and yohimbine increased the turnover rate both in the corpus striatum and in the tuberculum olfactorium. Azapetine, phentolamine and tolazoline as well as the beta-adrenoceptor antagonist propranolol were without a significant effect, whereas the DA antagonist haloperidol increased DOPAC and HVA levels and decreased the levels of DA itself. The possibility that the yohimbine-induced increase in the DA turnover rate was produced by a direct blockade of DA autoreceptors, was investigated under conditions where influences other than those elicited via DA autoreceptors are thought to be eliminated, i.e. in rats treated with reserpine or gamma-butyrolactone (GBL). In rats that were pretreated with reserpine, yohimbine (10 mg/kg i.p.) was found to be ineffective in antagonizing the reduction of the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following decarboxylase inhibition, that was produced by the DA agonist apomorphine (2.0 mg/kg i.p.). In rats pretreated with reserpine, yohimbine (10 mg/kg i.p.) was also ineffective in antagonizing the reduction of the DOPAC and HVA levels produced by apomorphine (2.0 mg/kg i.p.), but it was effective in antagonizing the reduction of the HVA level that was produced by the selective DA autoreceptor agonist N,N-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT, 1.0 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Psychotomimetic opiate receptors labeled and visualized with (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine.

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-[3H]3-PPP in brain. The drug specificity of (+)-[3H]3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-[3H]3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10,047 at the sigma site, opposite to the stereoselectivity seen at mu, delta, and kappa opiate receptors. (+)-[3H]3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-[3H]3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-[3H]3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavioral effects of 3-PPP.

On the presence of autoreceptors on dopamine neurons in different brain regions.

The alpha-methyltyrosine-induced disappearance of dopamine was inhibited by the selective dopamine autoreceptor agonist B-HT 920 in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex, and the rostral part of the cerebral cortex of the rat. These inhibitory actions of B-HT 920 were almost completely reversed by the dopamine receptor antagonist haloperidol, indicating that they were caused by a stimulation of dopamine autoreceptors. In the caudal cortex and the cerebellum, the effects of B-HT 920 and haloperidol were less clear, perhaps due to a low concentration of dopamine and to the occurrence of this dopamine in both dopamine and noradrenaline neurons. In the hypothalamus, B-HT 920 and haloperidol did not change the alpha-methyltyrosine-induced disappearance of dopamine in agreement with previous findings that the tubero-infundibular dopamine neurons are not regulated via dopamine receptors.

Demonstration of autoreceptors on dopamine neurons in different brain regions of rats treated with gammabutyrolactone.

Following interruption of the nerve impulse flow in the dopamine neurons by treatment with gammabutyrolactone, the selective dopamine autoreceptor agonist B-HT 920 reduced the DOPA accumulation after DOPA decarboxylase inhibition and the 3,4-dihydroxyphenylacetic acid concentration in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex and the rostral part of the cerebral cortex of rats. The effects were completely inhibited by the dopamine receptor antagonist haloperidol, indicating that they were caused by stimulation of dopamine autoreceptors. In the caudal part of the cerebral cortex and the cerebellum, B-HT 920 somewhat reduced the concentration of dihydroxyphenylacetic acid via a haloperidol-sensitive mechanism, suggesting that there are a few dopamine neurons with autoreceptors in these regions. No evidence was obtained for the presence of autoreceptors on the dopamine neurons in the hypothalamus. The gammabutyrolactone-induced elevation of the dopamine concentration was not reduced by B-HT 920 in any region, suggesting that this effect of gammabutyrolactone was caused by decreased release rather than increased synthesis of dopamine under our experimental circumstances.

Electrophysiological studies on EMD 23 448, an indoly l-3-butylamine, in the rat: A putative selective dop amine autoreceptor agonist

Single unit electrophysiological and microiontophoretic techniques were used to study the effects of a putative selective dopamine autoreceptor agonist, EMD 23 448, an indolyl-3-butylamine on the activity of both dopamine neurons in the substantia nigra and dopamine-sensitive neurons in the caudate nucleus. Intravenous administration of EMD 23 448 inhibited the firing of dopamine neurons in the nigra in a dose-dependent manner. This effect could be readily reversed by the subsequent intravenous administration of the dopamine receptor antagonist, haloperidol. Microiontophoretic application of EMD 23 448 onto these neurons also inhibited their activity and this effect was blocked by iontophoresis of the dopamine receptor antagonist, trifluoperazine. Intravenous administration of the former compound increased the activity of dopamine-sensitive cells in the caudate in the same doses which inhibited dopamine neurons in the nigra. However, this effect appeared to be indirect since the iontophoretic application of EMD 23 448 directly onto caudate neurons had no effect on their firing rate. In addition, the activity of norepinephrine-containing neurons in the locus coruleus and serotonin-containing cells in the dorsal raphé nucleus was not changed by direct microiontophoretic application of this compound. In contrast, EMD 23 448 selectively blocked the acetylcholine-induced activation of pyramidal neurons in the hippocampus. These findings provide further evidence that with respect to central catecholamine neurons EMD 23 448 may be a selective agonist for dopamine autoreceptors.

Different actions of TL-99 and 3-PPP in producing contraversive turning in the 6-OHDA-lesioned rat

The putatively selective dopamine autoreceptor agonists TL-99 and 3-PPP were compared with apomorphine for the production of contraversive turning in the 6-hydroxydopamine-lesioned rat. Although less potent than apomorphine, 3-PPP produced dose-related contralateral turning. The contralateral turning produced by TL-99 plateaued at the 3 mg/kg i.p. dose level. Yohimbine significantly enhanced the TL-99-induced turning, whereas it failed to modify the 3-PPP turning. The results suggest that the α 2-adrenergic properties of TL-99 at doses of > 3.0 mg/kg masked its dopaminergic effects. Hence, 3-PPP is clearly the more selective agent for DA receptors.

3-PPP antagonizes the in vitro effects of D-1 and D-2 dopamine receptor agonists in rat neostriatum

3-PPP has been reported to be a selective dopamine autoreceptor agonist, a conclusion based on in vivo studies. In rat neostriatum in vitro however, 3-PPP antagonized concentration-dependently the stimulation of cyclic AMP efflux caused by the D-1 receptor agonist SKF 38393 and the inhibition of K +-induced [ 3H]acetylcholine release caused by the D-2 receptor agonist LY 141865. 3-PPP alone did not affect [ 3H]acetylcholine release or cyclic AMP efflux. When interpreting the effects of 3-PPP in vivo dopamine receptor antagonism should be considered.

Trans-N-n-propyl-7-hydroxy-octahydrobenzo(f)quinoline, a rigid 3-PPP analogue with greater potency but lack of selectivity for dopamine autoreceptors

trans- and cis-7-hydroxy-octahydrobenzo(f)quinoline were synthesized as analogues of the selective dopamine autoreceptor agonist 3-PPP. The trans compound appeared more effective than 3-PPP in the dopamine autoreceptor test model, but it also exhibited postsynaptic dopamine receptor stimulating activity. The cis compound was inactive in both these test models. It is concluded that in the trans compound the dopamine autoreceptor stimulating potency of 3-PPP has been much enhanced at the cost of dopamine autoreceptor selectivity.

Postynaptic dopamine agonist properties of TL-99 are revealed by yohimbine co-treatment

The claim that TL-99 (6,7-dihydroxy-2-dimethylaminotetralin hydrobromide) is a selective dopamine autoreceptor agonist relies partly upon indirect behavioral evidence, particularly the absence of stereotyped behavior in treated rats. The possibility was examined that concurrent α 2-adrenoceptor agonist properties of TL-99 could have masked postsynaptic dopamine agonist activity. Co-administration of yohimbine or piperoxan with a high dose of TL-99 (30 mg/kg) dramatically increased motor activity in reserpinized rats, whereas each drug by itself had no effect. Contralateral rotational behavior in 6-hydroxydopamine-lesioned rats resulted from combined treatment with yohimbine and a high dose of TL-99 (30 mg/kg) but appeared to be suppressed by concurrent flaccidity if TL-99 was given by itself. Yohimbine failed to alter the effects of 3-PPP (N-n-propyl-3-(3-hydroxyphenyl)-piperidine), another putative dopamine autoreceptor agonist, in either model of postsynaptic dopamine agonism. It is concluded that a concurrent behaviorally depressant action of TL-99, possibly α 2-agonism, masks the stimulation of postsynaptic dopamine receptors by high doses of TL-99.

A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine).

In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and alpha-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and alpha-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were most sensitive to the activating effects of d-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25 micrograms/kg) potentiated the locomotor stimulant effects of d-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or alpha-adrenergic receptor sensitivity. The increased sensitivity to d-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by the d-amphetamine due to the DA autoreceptors having become subsensitive.

Pharmacological profiles of the putative dopamine autoreceptor agonists 3-PPP and TL-99

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6,7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [ 3H]apomorphine and [ 3H]spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the γ-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. Clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCl-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and α-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.