Article

Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5HT6 ligands with significant selectivity for D3 over D2 receptors

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Abstract

All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2AR antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5HT6 receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R vs D2R and likewise recognize 5HT6R. Starting from the high affinity 5HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5HT6R ligands with significant selectivity for D3R over D2R.

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... Finally, a focus has also been put on developing multi-target compounds that bind to the 5-HT 6 receptor and other receptors. For example, in an effort to find drugs that could control cognitive symptoms in patients with schizophrenia, dual 5-HT 6 receptor/dopamine D 3 receptor antagonists have been developed (Grychowska et al., 2019;Saavedra et al., 2017). Interestingly, the compound 19 synthetized by Grychowska and colleagues is a neutral 5-HT 6 receptor antagonist as well as a high-affinity D 3 receptor antagonist (Grychowska et al., 2019). ...
Thesis
La mise en place des circuits neuronaux est un processus complexe et finement régulé. Lorsque ce processus est altéré, des pathologies neurodéveloppementales telles que la schizophrénie ou les troubles du spectre de l’autisme apparaissent, dont la prise en charge thérapeutique est à ce jour insuffisante. Le récepteur 5-HT6 de la sérotonine est une cible thérapeutique intéressante pour le traitement des déficits cognitifs associés à ces pathologies. Cependant les mécanismes qui sous-tendent son rôle dans le neurodéveloppement ne sont pas complètement élucidés. En effet, l’étude des fonctions du récepteur 5-HT6 in vivo est à ce jour compliquée, car sa localisation exacte dans le système nerveux central est encore mal connue. Cette méconnaissance résulte de l’absence d’anticorps spécifiques permettant de réaliser des études d’immunomarquage in vivo. Mon travail de thèse a permis de contourner ce problème et de réaliser une cartographie complète de l’expression du récepteur 5-HT6 au cours du développement, grâce à l’utilisation d’un modèle murin de souris knock-in exprimant le récepteur 5-HT6 portant une étiquette fluorescente (GFP). Cette étude a permis de mettre en évidence non seulement les structures mais également les types cellulaires qui expriment le récepteur. J’ai ainsi pu déterminer que le récepteur est exprimé très tôt dans le développement, et que son expression persiste à l’âge adulte. On le retrouve aussi bien dans les neurones de projection que dans les astrocytes, où il est localisé de façon prépondérante dans le cil primaire, un organite impliqué dans divers phénomènes développementaux incluant la migration neuronale. Des animaux knock-out qui n’expriment plus le récepteur 5-HT6 présentent des cils raccourcis, indiquant un rôle du récepteur dans les fonctions ciliaires. De façon intéressante, j’ai pu montrer que cette localisation subcellulaire, conforme à ce qui a été décrit dans la littérature, est fortement modifiée pendant les 10 premiers jours post-nataux, où le récepteur se trouve majoritairement relocalisé dans le compartiment somato-dendritique. Cette relocalisation du récepteur au niveau du soma semble essentielle à son interaction avec certains de ses partenaires, comme GPRIN1. In vitro, le complexe formé par GPRIN1 et le récepteur promeut la complexification de l’arborisation dendritique. Mon travail a permis de mettre en évidence in vivo l’interaction entre GPRIN1 et le récepteur 5-HT6 au niveau de la membrane du soma des neurones, dans des tranches de cerveau de souris au stade post-natal. Enfin, j’ai démontré que l’inhibition pharmacologique de l’activité constitutive du récepteur par des composés agonistes inverses durant la période post-natale induit des déficits comportementaux de sociabilité mesurés à l’adolescence. Cela suggère un rôle critique de l’activité constitutive du récepteur spécifiquement pendant les premiers jours du neurodéveloppement postnatal, lorsqu’il est localisé dans le compartiment somato-dendritique. Ainsi, mon travail de thèse a permis de caractériser précisément la localisation du récepteur au cours du développement, du stade embryonnaire à l’adulte. Une découverte majeure de mon travail est la relocalisation dynamique du récepteur du cil vers le compartiment somato-dendritique au cours de la période post-natale et le fait que l’inhibition de l’activité constitutive du récepteur durant cette période induit une altération du comportement social. Cette observation originale pourrait expliquer le rôle clé joué par le récepteur à cette période critique du développement neuronal. Cette étude forme une base solide pour de futures recherches sur les fonctions du récepteur 5-HT6 au cours du développement et chez l’adulte et confirme son intérêt comme cible thérapeutique dans le cadre des pathologies neurodéveloppementales.
... MTDLs have been reported, with the most prominent examples being dual enzymatic inhibition of acetylcholinesterase (AChE) and glycogen synthase kinase (GSK-3β), 7 inhibition of AChE and monoamine oxidase B (0) 8 and inhibition of β-secretase (BACE-1) and GSK-3β. 9 The MTDL strategy is further completed with GPCRs dual-acting compounds as 5-HT6/D3 and 5-HT2A/5-HT6 receptor antagonists [10][11][12][13] as well as 5-HT4R agonist/5-HT6R antagonist. 14 However, simultaneous targeting of enzyme and receptor activities constitutes a more challenging area. ...
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The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking 5-HT6R scaffolds with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
... Multifunctional drugs, combining several pharmacological effects in a single molecule, constitute a promising strategy for the treatment of multifactorial neurodegenerative and psychiatric diseases. Compounds reported in literature that simultaneously bind to 5-HT 6 R and D 3 R neither display high affinity for both targets 31 nor show activity in functional assays. 32,33 In the present study, compound CPPQ, a neutral 5-HT 6 R antagonist, was structurally modified with various alkyl substituents at the nitrogen atom of pyrrolidine, in order to obtain dual 5-HT 6 / D 3 R ligands ( Figure 2). ...
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In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT6 and dopamine D3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist of 5-HT6R, as a chemical template for designing dual antagonists of 5-HT6/D3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT6 and D3 receptors. The study identified compound 19 ((S)-1-((3-chlorophenyl)sulfonyl)-N-(1-isobutylpyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine), which was classified as a dual 5-HT6/D3Rs antagonist (Ki (5-HT6) = 27 nM, Ki (D3) = 7 nM). Compound 19 behaved as a neutral antagonist at Gs signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk-5)-dependent neurite growth. In contrast to the well characterized 5-HT6R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicine, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into pro-cognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.
... One promising candidate would be blockade of dopamine D 3 receptors (Saavedra et al., 2016) since: (1) this mechanism consistently reinforces frontocortical (though not hippocampal) cholinergic transmission; (2) in contrast to antagonism of D 2 receptors which denigrates cognitive performance, blockade of D 3 receptors in the FCX is associated with a remarkably broadbased and robust pattern of pro-cognitive activity in rodent and primate models of pro-cognitive properties: moreover, pro-cognitive actions are at least partly expressed in the FCX and (3) the potential antipsychotic properties of D 3 receptor blockade would be of utility in the treatment of both schizophrenia and Alzheimer's disease, as well as psychotic depression (Gross et al., 2013;Loiseau and Millan, 2009;Millan and Brocco, 2008;Millan et al., 2007a;Nakajima et al., 2013;Watson et al., 2012). It is, thus, of interest that sub-maximal and just effective doses of 5-HT 6 and D 3 receptor antagonists cooperatively elevated levels of ACh in the FCX (Figure 9). ...
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A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi = 8.4, DA D2 pKi = 6.0 and hERG fpKi = 5.2) showed a balanced profile and further refinements are in progress around this molecule.
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The seminal human dopamine D3 receptor (hD3R) ligand BP 897 has shown interesting properties during clinical trials. However, its lack of selectivity towards human adrenergic receptor impedes further development. Two approaches were followed to increase hD3R selectivity. The lead optimisation succeeded, we disclose here ligands with subnanomolar potency for D3R, combined with a good selectivity for the closely related human dopamine D2 and human adrenergic alpha-1 receptors.
Article
Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer's disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development. Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words '5-HT6', 'cognition', 'dementia', 'Alzheimer's disease', 'Phase II' and 'Phase III' in various databases and from conference abstracts. Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.
Article
Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a “generalized deficit”, in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM-5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.
Article
Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socio-economic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This perspective reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant pro-cognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.
Article
New and efficient synthetic approach to benzocyclobutene derivatives is described. Halogen-lithium exchange of ortho-halo aryl triflates (THF, -78°C) quickly generates arynes which react with the coexisting ketene silyl acetals to give [2+2] cycloadducts in high yields. The polarization of the aryne species induced by an adjacent alkoxyl group (inductively electron withdrawing) directs the regioselectivity of the cycloadditions. Subsequent acetal cleavage under acidic conditions gives various benzocyclobutenones in high yields.
Article
The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. None.
Article
Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D3 receptors in cognition, and propose dopamine D3 receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D3 receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D3 receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D3 receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D3 receptor blockade appears to enhance while D3 receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D3 receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D3 receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.
Article
The first observation of the stereospecificity in the benzyne-olefin [2 + 2] cycloaddition is described. The key points reside in (1) the efficient method for generating benzyne species by the halogen-lithium exchange reaction of ortho-halo aryl triflates, and (2) the choice of ketene silyl acetal as the partner olefin.
Article
Antipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission.TDincreases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as firstline treatment represents the best course for schizophrenia and most likely other settings where APDs are used. Expected final online publication date for the Annual Review of Medicine Volume 64 is January 07, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Article
A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the regioselective [2+2] cycloaddition of -alkoxybenzynes and ketene silyl acetals. The cycloadducts could be converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.
Article
The dopamine D3 receptor (D3R) has been implicated in substance abuse and other neuropsychiatric disorders. The high sequence homology between the D3R and D2R, especially within the orthosteric binding site (OBS) that binds dopamine, has made the development of D3R-selective compounds challenging. Here, we deconstruct into pharmacophoric elements a series of D3R-selective substituted-4-phenylpiperazine compounds and use computational simulations and binding and activation studies to dissect the structural bases for D3R selectivity and efficacy. We find that selectivity arises from divergent interactions within a second binding pocket (SBP) separate from the OBS, whereas efficacy depends on the binding mode in the OBS. Our findings reveal structural features of the receptor that are critical to selectivity and efficacy that can be used to design highly D3R-selective ligands with targeted efficacies. These findings are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands.
Article
Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D(3) receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.01-0.63 mg/kg s.c.) blocked a delay-induced impairment of novel object recognition in rats, a model of visual learning and memory. Further, S33138 (0.16-2.5 mg/kg s.c.) similarly reduced a delay-induced deficit in social novelty discrimination in rats, a procedure principally based on olfactory cues. Adult rhesus monkeys were trained to perform cognitive procedures, then chronically exposed to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which produced cognitive impairment without motor disruption. In an attentional set-shifting task of cognitive flexibility involving an extra-dimensional shift, deficits were reversed by S33138 (0.04 and 0.16 mg/kg p.o.). S33138 also significantly improved accuracy (0.04 and 0.16 mg/kg p.o.) at short (but not long) delays in a variable delayed-response task of attention and working memory. Finally, in a separate set of experiments performed in monkeys displaying age-related deficits, S33138 significantly (0.16 and 0.63 mg/kg p.o.) improved task accuracies for long delay intervals in a delayed matching-to-sample task of working memory. In conclusion, S33138 improved performance in several rat and primate procedures of cognitive impairment. These data underpin interest in D(3) receptor blockade as a strategy for improving cognitive performance in CNS disorders like schizophrenia and Parkinson's disease.
Article
In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH(3)-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K(i) = 1 nM) for D3 and approximately 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.
Article
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Article
In vivo animal models are indispensable both for clarifying the pathological bases of schizophrenia, and for evaluating the potential benefits and disadvantages of novel therapy. Procedures that model mnemonic impairment are of particular interest since currently-available drugs do little to improve cognitive symptoms: this is hardly surprising, in fact, since most of them potently antagonise histamine H(1), muscarinic, and/or alpha(1)-adrenergic receptors. Further, their blockade of D(2) receptors likewise compromises cognitive performance. By contrast, D(3) receptor antagonism improves certain cognitive domains, suggesting that preferential antagonism of D(3) vs. D(2) receptors may permit enhanced effectiveness against cognitive dysfunction. The novel agent, S33138, possesses such an "optimised" profile and shows a unique and broad-based pattern of pro-cognitive properties in rodents and primates, in the absence of extrapyramidal and metabolic side-effects. The present article surveys the preclinical pharmacology of S33138. It also reviews developmental and genetic risk factors for schizophrenia and their experimental modeling in rodents, with a particular emphasis on sensorimotor gating and cognitive deficits.
Article
We have used the polymerase chain reaction technique to selectively amplify a guanine nucleotide-binding protein-coupled receptor cDNA sequence from rat striatal mRNA that exhibits high homology to previously cloned serotonin receptors. Sequencing of a full length clone isolated from a rat striatal cDNA library revealed an open reading frame of 1311 base pairs, encoding a 437-residue protein with seven hydrophobic regions. Within these hydrophobic regions, this receptor was found to be 41-36% identical to the following serotonin [5-hydroxytryptamine (5-HT)] receptors: 5-HT2 > 5-HT1D > 5-HT1C > 5-HT1B > 5-HT1A > 5-HT1E. Northern blots revealed a approximately 4.2-kilobase transcript localized in various brain regions, with the following rank order of abundance: striatum > olfactory tubercle > cerebral cortex > hippocampus. Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of (+)-[2-125I] iodolysergic acid diethylamide ([125I]LSD) with a Kd of 1.26 nM. Among endogenous biogenic amines, only 5-HT completely inhibited [125I]LSD binding (Ki = 150 nM). The inhibition of [125I]LSD binding by other serotonergic agonists and antagonists revealed a pharmacological profile that does not correlate with that of any previously described serotonin receptor subtype. In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs, including clozapine, amoxipine, and amitriptyline. In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylyl cyclase activity, which is blocked by antipsychotic and antidepressant drugs. The distinct structural and pharmacological properties of this receptor site indicate that it represents a completely novel subtype of serotonin receptor. Based on its affinity for tricyclic psychotropic drugs and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.
Article
A full-length cDNA clone of the human dopamine D3 receptor was obtained by the polymerase chain reaction (PCR) using reverse-transcribed RNA from human brain as the template. The cDNA was inserted into an expression vector which was then stably transfected into either Chinese hamster ovary (CHO), SK-N-MC human epithelioma or mouse CCL1.3 fibroblast cell lines. Post-transfection, the Bmax for D3 receptor expression was 1.9, 1.1 and 0.4 pmol/mg protein in the CHO-K1, SK-N-MC and CCL1.3 cell lines, respectively. The D3 receptor expressed in CHO-K1 and CCL1.3 cells exhibited similar radioligand binding profiles, especially for the D3-selective compound, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT). Radioligand-binding competition curves of presumed D3 agonists were shifted to the right by the addition of guanine nucleotides and Na+ to the assay buffer. Presumed D3-receptor agonists had no effect on cAMP accumulation in any of the D3-transfected cell lines although cAMP accumulation was inhibited by dopamine D2 receptor activation in D2-transfected CHO and CCL1.3 cells and by activation of the exogenously expressed neuropeptide Y receptor in SK-N-MC cells. Also, D3 receptor activation neither potentiated ATP-stimulated arachidonic acid release from CHO cells nor stimulated inositol phosphate production in CCL1.3-cells although both of these responses were elicited by D2 agonists in D2-transfected cells. We conclude that the signalling properties of the D3 receptor differ from those of its closest homolog, the D2 receptor.
Article
The effects of a number of D2-like dopamine receptor antagonists have been determined on forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing the human D2short dopamine receptor (CHO-D2S cells). Dopamine inhibited the effect of forskolin (as expected for a D2 receptor). However, all of the antagonists tested, apart from UH232 and (−)-butaclamol, were able to increase cyclic AMP accumulation above the forskolin control level. (+)-Butaclamol elicited a similar stimulation of forskolin-stimulated cyclic AMP accumulation in a CHO cell line expressing human D2long dopamine receptors whereas it exhibited no stimulating effect on forskolin-stimulated cyclic AMP accumulation in untransfected CHO-K1 cells. There was a strong correlation between the EC50 values of these compounds for potentiation of cyclic AMP accumulation and their Ki values from radioligand binding experiments in CHO-D2S cells. The effects of both (+)-butaclamol and dopamine in CHO-D2S cells were inhibited by pre-treatment with pertussis toxin indicating a role for Gi/Go proteins. UH232 did not significantly affect forskolin-stimulated cyclic AMP accumulation but this substance was able to inhibit the effects of both dopamine and (+)-butaclamol in a concentration-dependent manner. Thus the effects of (+)-butaclamol on forskolin-stimulated cyclic AMP accumulation are mediated directly via the D2 receptor rather than by reversal of the effects of an endogenous agonist. These data suggest that the D2 dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D2 dopamine receptors. British Journal of Pharmacology (1997) 121, 731–736; doi:10.1038/sj.bjp.0701196
Article
A new series of benzopyrano[3,4-c]pyrrole derivatives were synthesized and evaluated for their interaction with dopamine D3 versus D2 receptors. Amongst these compounds, 4x (S 33084) was found to be a potent and selective dopamine D3 receptor antagonist.
Article
The dopamine D(3) receptor has been recognized to play an important role in the molecular mechanisms of various neuropsychiatric disorders. The development of new dopamine D(3) receptor selective antagonists is premised on the potentially improved therapeutic treatment of psychosis like schizophrenia. Partial agonists at dopamine D(3) receptors are supposed to be beneficial when administered to drug abusers or in Parkinson's disease. The structural basis for most compounds is at least a basic, aryl-substituted alkanamine part with an alkyl moiety, which in many compounds forms a spacer to another aryl residue. Structural variety among the amine moiety includes aminotetralins, tetrahydroisoquinolines, isoindoles, benzazepines, and aminoindans, as well as pyrrolidines, pyrroles, and 4-phenylpiperazines. Various ways for lead optimization are shown in different classes of compounds. Promising ligands with high D(3) receptor affinity often lack sufficient selectivity or display deficits in the required in vivo parameters. Structure-activity relationships for dopamine D(3) receptor antagonists and partial agonists are discussed here, along with the outlook for their potential therapeutic application.
Article
A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.
Article
A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
Article
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Article
Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D(3) versus D(2) receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D(3) receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D(2) receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+)S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D(3) receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D(3) receptors as a target for treatment of disorders in which cognitive function is compromised.
Article
GPCR-focused compound libraries were designed by strategic iterative virtual screening. The most potent ligands yielded Ki values of 65 nm at the dopamine D3 receptor subtype. Two potential binding modes were observed for receptor antagonists in a homology-based model of the dopamine D3 receptor. Results demonstrate opportunities for a combination of different virtual screening methods in early stages of GPCR drug discovery for new lead finding. (Figure Presented)
Article
5-HT6 receptor antagonists improve cognitive processes in rodents. However, their site(s) of action remains unexplored and their influence upon social memory has been little investigated. We examined the influence of 5-HT6 receptor ligands upon social memory in rats by use of systemic or local administration into the frontal cortex (FCX), striatum, or nucleus basalis magnocellularis (NBM). The social recognition test is based upon the ability of an adult rat to recognize a younger conspecific during the second of two 5-min sessions. In a procedure without an inter-session interval, the actions of drugs alone and the ability to reverse "amnesia" induced by the muscarinic antagonist, scopolamine (1.25 mg/kg, s.c.), were examined. The potential promnesic effect of drugs was also investigated in another procedure where a spontaneous deficit of recognition was induced by a 120-min inter-session interval. The 5-HT6 receptor agonist, WAY-181187 (10.0 mg/kg, i.p.), significantly impaired social recognition. This effect was abolished by the 5-HT6 receptor antagonists, SB-271046 (20.0 mg/kg, i.p.) and SB-258585 (10.0 mg/kg, i.p.). These agents also abolished scopolamine-induced amnesia (10.0 and 2.5 mg/kg, i.p., respectively) and reversed the delay-induced deficit (10.0-20.0 and 2.5-10.0 mg/kg, i.p., respectively). WAY-181187 into the FCX significantly impaired social recognition (0.16-0.63 microg/side). Conversely, SB-271046 into the FCX (2.5-5.0 microg/side), but neither into the striatum nor the NBM, significantly reversed spontaneous deficit. These results indicate that 5-HT6 receptors modulate social recognition by actions in the FCX and underpin their pertinence as targets for the treatment of psychiatric disorders in which cognitive function is compromised.