(+)- and (−)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis

doi:10.1016/0014-2999(84)90694-0

European Journal of Pharmacology

Volume 106, Issue 1, 30 October 1984, Pages 185-189

https://doi.org/10.1016/0014-2999(84)90694-0 Get rights and content

Abstract

Both enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP; 0.5–32 mg/kg s.c.) dose dependently reduced the increase in striatal dopamine (DA) synthesis rate produced by γ-butyrolactone (GBL). Whereas (+)-3-PPP completely prevented the action of GBL, (−)-3-PPP was only partially effective. In addition, (−)-3-PPP partially antagonised the inhibitory action of apomorphine on the GBL-induced increase in DA synthesis rate. These findings suggest that (+)- and (−)-3-PPP act as full and partial agonists respectively, at striatal DA autoreceptors controlling DA synthesis.

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Cited by (34)

A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro
2012, European Journal of Pharmacology
Citation Excerpt :
In contrast (−)-3-PPP did not have inhibitory effects on dopamine release but antagonized those effects of (+)-3-PPP. Both enantiomers can reduce increases in striatal dopamine synthesis produced by γ-butyrolactone, although the (−)enantiomer was only partially active (Clark et al., 1984). 3-PPP has also been shown not to protect against MPTP-induced dopaminergic neurotoxicity (Muralikrishnan et al., 2004).
The effects of aripiprazole, (−)-(3-hydroxyphenyl)-N-n-propylpiperidine ((−)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (−)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10 nM to 10 μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10 μM for aripiprazole. Both compounds were tested against the concentration–response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (−)-3-PPP shifted the concentration–response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10 μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D₂ ligands remains controversial.
Pre- and postsynaptic actions of a partial D2 receptor agonist in reserpinized young rats: Longevity of agonistic effects
2006, Brain Research
Citation Excerpt :
In terms of synthesis modulating autoreceptors, a single pretreatment injection of reserpine (a dopamine depleting agent) is sufficient to induce a state in which partial D2 agonists inhibit, rather than enhance, striatal dopamine synthesis (Hjorth et al., 1983, 1988; Svensson et al., 1991; Yoshida et al., 2006). Partial D2 agonists cause a similar inhibition of dopamine synthesis when preweanling and adult rodents are pretreated with the nerve impulse flow inhibitor γ-butyrolactone (GBL) (Clark et al., 1985c; Hjorth et al., 1983; Oshiro et al., 1998; Svensson et al., 1991; Yoshida et al., 2006). Conversely, a more substantial and prolonged dopamine depletion is necessary before a partial D2 agonist causes agonistic effects at postsynaptic dopamine receptors (Arnt and Hyttel, 1984; Clark et al., 1985b; McDougall et al., 2005; Wacan et al., 2006; Wachtel et al., 1984).
Partial D2 receptor agonists (e.g., terguride, preclamol, and aripiprazole) have antagonist-like effects at normosensitive D2 postsynaptic receptors and synthesis modulating autoreceptors. In reserpine-pretreated adult and young rats, however, partial D2 agonists function like high efficacy agonists at D2 postsynaptic receptors and autoreceptors (i.e., terguride increases locomotor activity and decreases dopamine synthesis). The purpose of the present study was to examine the time-course of these pharmacological effects. In all experiments, preweanling rats were given daily injections of reserpine (1 mg/kg, i.p.) or vehicle on postnatal day (PD) 16–PD 20. In the dopamine synthesis experiments, the ability of terguride (0.8 mg/kg) to reduce striatal DOPA accumulation (in NSD-1015 treated rats) was assessed either 5 h or 1, 2, 4, or 8 days (Experiment 1) or 4, 8, 12, 16, 20, or 24 days (Experiment 2) after reserpine pretreatment. In the behavioral experiments, locomotor activity of vehicle or terguride (0.8 mg/kg, i.p.) treated rats was assessed 5 h or 1, 2, 4, or 8 days after the 5-day reserpine regimen. Results from the dopamine synthesis experiments showed that terguride caused agonist-like effects (i.e., decreased DOPA accumulation) at only the 5 h and 1 day time points, although terguride did not induce its normal antagonist-like effects even 20 days after reserpine pretreatment. In the behavioral experiments, terguride stimulated locomotor activity for only the initial 2 days after reserpine pretreatment. The results of the present study show that the agonistic effects of terguride at pre- and postsynaptic receptors are short-lived, but terguride may not exhibit normal antagonistic effects, at least at synthesis modulating autoreceptors, until long after conclusion of reserpine pretreatment.
Partial agonism of dopamine, serotonin and opiate receptors for psychiatry
2006, Drug Discovery Today: Therapeutic Strategies
Most psychiatric diseases are treated with pharmacological receptor antagonists. The efficacy of recently approved partial agonists and their relatively good safety profiles suggest an alternative strategy for drug discovery. Aripiprazole (Abilify) treats schizophrenia through partial agonism of D_2/3 dopamine receptors, buspirone (Buspar) treats anxiety or depression by partial agonism of the 5-HT_1A receptor and partial opiate or dopamine agonists treat opiate and stimulant addictions. Predictions of other receptor targets for intervention by partial agonists provide a test for the broader utility of this pharmacological approach.
Effects of a partial D<inf>2</inf>-like receptor agonist on striatal dopamine autoreceptor functioning in preweanling rats
2006, Brain Research
Citation Excerpt :
In addition to using reserpine, a functional state of low dopaminergic tone can be induced by pretreating rats with the nerve impulse inhibitor γ-butyrolactone (GBL). In adult rats, both full and partial D2-like agonists inhibit the GBL-induced increase in DOPA accumulation: actions that are blocked by haloperidol (Clark et al., 1985c; Hjorth et al., 1983; Svensson et al., 1991). At present, no studies have examined whether administering partial D2-like agonists to preweanling rats affects autoreceptor-mediated functioning in an adult-typical manner.
There is evidence that partial D₂-like dopamine agonists (e.g., terguride) may not affect D₂-like postsynaptic receptors in an adult-typical manner during the preweanling period. To determine whether synthesis modulating dopamine autoreceptors are also affected in an adult atypical manner by partial D₂-like agonists, preweanling rats were treated either acutely or repeatedly with reserpine (low dopaminergic tone) or vehicle (high dopaminergic tone). The ability of terguride, quinpirole (a full D₂-like agonist), or haloperidol (a D₂-like antagonist) to alter striatal DOPA accumulation was assessed after NSD-1015 treatment on postnatal day (PD) 21. In a separate set of experiments, terguride's ability to modulate dopamine synthesis was assessed in rats treated with the nerve impulse flow inhibitor γ-butyrolactone (GBL). Results showed that both terguride and quinpirole reduced striatal DOPA accumulation during a state of low dopaminergic tone (i.e., after reserpine pretreatment). During a state of high dopaminergic tone (i.e., after vehicle pretreatment), terguride had similar effects as haloperidol and increased DOPA accumulation. Terguride, like quinpirole, partially inhibited the GBL-induced increase in striatal DOPA accumulation. When considered together, these results indicate that synthesis modulating D₂-like autoreceptors are functional during the late preweanling period, and they respond in an adult-typical manner to a partial D₂-like agonist.
Partial dopamine receptor agonists reverse behavioral, biochemical and neuroendocrine effects of neuroleptics in the rat: Potential treatment of extrapyramidal side effects
1993, Neuropharmacology
The partial DA receptor agonist preclamol, (−)-3-PPP (50–200 c, s.c.) partially reversed the catalepsy induced by the dopamine (DA) receptor antagonists haloperidol (5.3 μmol/kg, i.p.) and raclopride (20.1 μmol/kg, i.p.) in rats. Terguride (transdihydrolisuride), a partial DA receptor agonist with an efficacy lower than that of preclamol, blocked haloperidol (10.6 μmol/kg, i.p.) induced catalepsy at 5 μmol/kg, s.c., but not at 20 μmol/kg, s.c. The effects of terguride in this assay are possibly related to the compound's mixed partial DA agonist/5-HT_1A receptor agonist properties. The high efficacy agonist, pramipexole (SND 919) also blocked haloperidol induced catalepsy at 50 μmol/kg, s.c. Haloperidol (0.33–1.3 μmol/kg, i.p.) reduced the locomotor activity down to 5% of saline controls and elevated limbic and striatal DOPA accumulation. When combined with haloperidol, preclamol (100–200 μmol/kg, s.c.) antagonized both the strong hypomotility and increase in DOPA accumulation. Finally, the elevation of serum prolactin in rats induced by haloperidol (0.25 μmol/kg, i.p.) was significantly antagonized by co-administration of preclamol (39 μmol/kg, s.c.). These results show that partial DA agonists can reverse both behavioral, biochemical and neuroendocrine effects of neuroleptics. It also suggests the utility of partial DA receptor agonists in combination with classical neuroleptics in order to minimize the appearance of extrapyramidal side-effects and hyperprolactinemia.
Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors
1989, Pharmacology, Biochemistry and Behavior
The nonselective dopamine (DA) receptor agonists R(−)apomorphine (APO) and R(−)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED₅₀ values of 300 and 18 μg/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p<0.001) by pretreatment with sulpride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED₅₀. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserve for this response.

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Short communication(+)- and (−)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis

Abstract

European J. Pharmacol.

European J. Pharmacol.

Dopamine agonist and antagonist effects of the 3-PPP enantiomers

Psychopharmacology

Dopamine receptor agonists: intrinsic activity vs. state of the receptor

J. Neural Transm.

Short communication
(+)- and (−)-3-PPP exhibit different intrinsic activity at striatal dopamine autoreceptors controlling dopamine synthesis