osu-6162 and pridopidine

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Piperazines; Piperidines; Quinolones; Schizophrenia

Topics: Amphetamine; Animals; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; HEK293 Cells; Humans; Male; Piperidines; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Transfection; Tritium

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

Topics: Animals; Aripiprazole; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Hyperprolactinemia; Lactotrophs; Male; Methyltyrosines; Piperazines; Piperidines; Prolactin; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Binding, Competitive; Cell Line; Corpus Striatum; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Humans; Ligands; Male; Models, Chemical; Molecular Structure; Motor Activity; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

A new pharmacological class of CNS ligands with the unique ability to stimulate or suppress motor and behavioral symptoms depending on the prevailing dopaminergic tone has been suggested as "dopaminergic stabilizers". The molecular mode-of-action of dopaminergic stabilizers is not yet fully understood, but they are assumed to act via normalization of dopaminergic signaling, through interactions with the dopamine D(2) receptor. Here we have evaluated the dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162, as well as the new compound N-{[(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (NS30678) in a series of cellular in vitro dopamine D(2) receptor functional and binding assays. Neither ACR16, (-)-OSU6162, nor NS30678 displayed detectable dopamine D(2) receptor-mediated intrinsic activity, whereas they concentration-dependently antagonized dopamine-induced responses with IC(50) values of 12.9microM, 5.8microM, and 7.0nM, respectively. In contrast to the high-affinity typical antipsychotics haloperidol and raclopride, the dopaminergic stabilizers ACR16 and (-)-OSU6162 both displayed fast dopamine D(2) receptor dissociation properties, a feature that has previously been suggested as a contributing factor to antipsychotic atypicality and attributed mainly to low receptor affinity. However, the finding that NS30678, which is equipotent to haloperidol and raclopride, also displays fast receptor dissociation, suggests that the agonist-like structural motif of the dopaminergic stabilizers tested is a critical dissociation rate determinant. The results demonstrate that dopaminergic stabilizers exhibit fast competitive dopamine D(2) receptor antagonism, possibly allowing for temporally variable and activity-dependent dopamine D(2) receptor occupancy that may partly account for their unique stabilization of dopamine dependent behaviors in vivo.

Topics: Cell Line; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Kinetics; Ligands; Piperidines; Receptors, Dopamine D2

BACKGROUND AND PURPOSE; The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D(2) dopamine receptor in vitro.. The affinities of these compounds for the D(2) dopamine receptor were evaluated in competition with [(3) H]spiperone and [(3) H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [(35) S]GTPγS binding.. Both compounds had low affinities for inhibition of [(3) H]spiperone binding (pK(i) vs. [(3) H]spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [(35) S]GTPγS binding when assayed in the presence of Na(+) ions, but if the Na(+) ions were removed, both compounds were low-affinity, partial agonists (E(max) relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [(35) S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [(3) H]NPA dissociation from D(2) dopamine receptors, indicating some allosteric effects of this compound.. The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D(2) dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed.. This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Dopamine Agonists; Humans; Piperidines; Protein Binding; Receptors, Dopamine D2

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

Topics: Animals; Brain; Dopamine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Habituation, Psychophysiologic; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Synaptic Transmission

"Dopamine stabilizers" are a new class of compounds that have the ability to reverse both hypo- as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (S)-(-)-3-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl)-piperidine [ACR16] although lacking high in vitro binding affinity for dopamine D2 receptor [(-)-OSU6162, Ki = 447 nM; ACR16, Ki > 1 microM], shows functional actions, suggestive of their interaction. Hence, we evaluated in vivo D2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose-dependent striatal D2 occupancy with ED50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (-)-OSU6162 and 35 to 74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (-)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Binding, Competitive; Dihydroxyphenylalanine; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Immunohistochemistry; Male; Motor Activity; Neostriatum; Nucleus Accumbens; Piperidines; Prolactin; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

Schizophrenia is manifested by positive and negative symptoms, as well as cognitive deficits. Most existing antipsychotic agents have poor effects on the negative symptoms of schizophrenia, thus emphasizing the necessity for developing new antipsychotic treatments. Dopaminergic stabilizers constitute one of the latest novelties in the quest for new antipsychotic drugs. Social withdrawal in rats, in response to treatment with NMDA-receptor antagonists such as (+)-MK-801, may be used to model negative symptoms. In this study we aimed to evaluate the dopaminergic stabilizers (-)-OSU6162 and ACR16, compared to haloperidol and clozapine, in a rat model for schizophrenia, focusing on (+)-MK-801 induced social withdrawal. Social behaviour and motor activity were assessed using a videotracking system, allowing automated analysis of the behaviour. Both (-)-OSU6162 and ACR16 were capable of restoring social behaviour, measured as proximity, to control level. These results indicate that these drugs may be effective in the treatments of negative symptoms.

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Haloperidol; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Schizophrenic Psychology; Social Behavior