Eltoprazine

Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverseeffect potential.[Pubmed:28379218]

Acta Neurobiol Exp (Wars). 2017;77(1):77-85.

Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L-DOPA-induced dyskinesia in animal models of Parkinson s disease (PD) and in dyskinetic PD patients. Much less is known about effects of Eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of Eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study. Given for 2 weeks either as infusion or as twice-daily treatment, Eltoprazine produced a decrease in food intake and body weight at doses leading to 200-500 nM plasma concentrations. In the elevated plus maze Eltoprazine increased anxietylike behavior. On the other hand, it induced a clearcut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test. Regarding adverse effects, Eltoprazine was found to produce hypothermia starting from 1 mg/kg. At s imilar doses it also increased locomotion in the open field. However, Eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg). In summary, effects of Eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects.

Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms.[Pubmed:26639853]

Neurobiol Dis. 2016 Feb;86:140-53.

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, Eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by Eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and Eltoprazine failed to recover it.

The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.[Pubmed:27866999]

Eur J Pharmacol. 2017 Jan 5;794:257-269.

The 5-HT1A/1B-receptor agonist Eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How Eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether Eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of Eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that Eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, Eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, Eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following Eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.

Discriminative stimulus properties of eltoprazine.[Pubmed:9200664]

Life Sci. 1997;61(1):11-9.

Rats were trained to discriminate Eltoprazine (1-(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazine) (1.0 mg/kg p.o.) from demineralized water in a two lever operant procedure. Eltoprazine generalized to the 5-HT1B receptor agonist anpirtoline (6-chloro-2-[piperidyl-4-thiol]-pyridine hydrochloride), the 5-HT(1A,1B) receptor agonists batoprazine (8-(1-piperazinyl)-2H-1-benzopyran-2-one) and 1-NP (1-(1-naphthyl)piperazine hydrochloride), and to the 5-HT(1B/2C) receptor agonist mCPP (1-(3-chlorophenyl)piperazine dihydrochloride). The 5-HT1A receptor agonist flesinoxan (R(+)-N-[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4-benzodioxin-5-yl) -1-piperazinyl]ethyl]-4-fluorobenzoamide) generalized partially and the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) failed to antagonize the Eltoprazine cue, suggesting that 5-HT1A receptors are of limited importance in the discriminative stimulus properties of Eltoprazine. Methiothepin, mCPP, mianserin and alprazolam did not antagonize the Eltoprazine cue. The 5-HT(1A,1B,1D) receptor agonist GR46611X (3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxy-benzyl)acrylam ide) and the 5-HT(1B,1D) receptor antagonist GR127935T (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide) did neither generalize to nor antagonize the Eltoprazine cue, whereas (-)-alprenolol showed partial antagonism and substitution. These results show that the Eltoprazine discriminative stimulus is mediated by the 5-HT1B receptor, although the lack of good 5-HT1B receptor antagonists weakens this conclusion.

Neurochemical profile of eltoprazine.[Pubmed:1982626]

Drug Metabol Drug Interact. 1990;8(1-2):85-114.

In this paper we present the neurochemical profile of Eltoprazine, a drug that specifically inhibits offensive aggression. Eltoprazine interacts selectively with serotonin (5-HT) receptor subtypes (Ki-values for 5-HT1A, 5-HT1B and 5-HT1C receptors are 40, 52 and 81 nM respectively). Affinity for other neurotransmitter receptors is much lower (Ki-values greater than 400 nM) than for 5-HT1 receptors. The selective interaction with 5-HT1 receptor subtypes is confirmed by in vitro autoradiographic studies using radiolabelled Eltoprazine. The overall distribution of [3H]Eltoprazine bears a strong resemblance to the localization of 5-HT1 binding sites labelled by [3H]5-HT, although some differences are observed. Eltoprazine (1 microM) inhibits the forskolin stimulated c-AMP production in hippocampus slices of the rat, indicating an agonistic action on the 5-HT1A receptor. The K+ stimulated release of 5-HT from rat cortex slices is inhibited by Eltoprazine (pD2 = 7.8). The maximal response, however, was clearly less than that of the full agonist 5-HT, indicating partial agonistic activity on the 5-HT1B receptor (alpha = 0.5). Eltoprazine has a weak antagonistic action (IC50 = 7 microM) on the 5-HT1C receptor as revealed by inhibition of the 5-HT-induced accumulation of inositol phosphates in the choroid plexus of the pig. In vivo, Eltoprazine reduces 5-HIAA levels in the striatum, without affecting the 5-HT levels. Eltoprazine also reduces the 5-HT synthesis rate as shown by 5-HTP accumulation after decarboxylase inhibition. These data indicate that Eltoprazine acts as a 5-HT agonist in vivo in a dose range that affects aggressive behaviour (0.3-3 mg/kg p.o.). Taken together from a variety of neurochemical studies there is strong evidence both in vitro and in vivo that the pharmacological actions of Eltoprazine can be attributed to an interaction with the 5-HT system, most probably via a (partial) agonistic action on 5-HT1A and 5-HT1B receptors.

Brain 5-HT and inhibition of aggressive behavior in animals: 5-HIAA and receptor subtypes.[Pubmed:2483273]

Psychopharmacol Bull. 1989;25(3):399-403.

Evolutionary constant serotonin (5-HT) neuronal systems evolved along medial brain structures; yet, wide variations in functionality characterize serotonergic systems in mediating aggressive responses in species ranging from lobsters, ants, electric fish, and rodents to primates. So far, the attempts to correlate cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels with measures of aggression have revealed inverse, direct, or no correlations in different nonhuman primate species. It is difficult to harmonize the occasional correlations between CSF 5-HIAA and adaptive aggressive acts in nonhuman primates (a) with clinically diagnosed suicidal or impulsive individuals, and (b) with the biochemical, anatomical, and presumably functional differentiation of 5-HT pathways and receptor subtypes. Eltoprazine, a mixed 5-HT1A/B agonist, and meta-trifluoro-methylphenyl-piperazine HCl (TFMPP), a more selective 5-HT1B agonist, specifically decrease aggressive behavior in several animal species and situations in both sexes without detriment to other social, exploratory, or motoric activities. A definite role for 5-HT1A, 5-HT2, and 5-HT3 receptor subtypes in the mechanisms mediating aggressive behaviors has to await the development of selective agonists and antagonists, respectively.

Eltoprazine hydrochloride (DU 28853 hydrochloride) is a serenic or antiaggressive agent which as an agonist at the 5-HT1A and 5-HT1B receptors and as an antagonist at the 5-HT2C receptor.

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