The synthesis and structure−activity relationship of a novel series of compounds with combined effects on 5-HT3A and 5-HT1A receptors and on the serotonin (5-HT) transporter (SERT) are described. ...Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT1A (K i = 15 nM), 5-HT1B (K i = 33 nM), 5-HT3A (K i = 3.7 nM), 5-HT7 (K i = 19 nM), and noradrenergic β1 (K i = 46 nM) receptors, and SERT (K i = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonist properties at 5-HT1B receptors, agonistic properties at 5-HT1A receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.
Brexpiprazole (OPC-34712, 7-{4-4-(1-benzothiophen-4-yl)piperazin-1-ylbutoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for ...serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.
Brexpiprazole (OPC-34712, 7-{4-4-(1-benzothiophen-4-yl)piperazin-1-ylbutoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) ...and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 (R)-(2,3-dimethoxyphenyl)1-(4-fluorophenethyl)piperidin-4-ylmethanol partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-2-4-(2-methoxyphenyl)-1-piperazinylethyl-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.
Brexpiprazole is a serotonin-dopamine activity modulator in clinical development for schizophrenia, adjunctive treatment of major depressive disorder, agitation in Alzheimer's disease and ...post-traumatic stress disorder. It is a partial agonist at 5-HT1A and D2 receptors with similar potency, and an antagonist at 5-HT2A and adrenergic α1B/2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5-HT1A receptors and displays less intrinsic activity at D2 receptors. This unique serotonin and dopamine modulatory activity has shown robust antipsychotic, antidepressant-like and anxiolytic activities, and limited extrapyramidal symptom liability with pro-cognitive efficacy in animal models. Phase III clinical trials have been successfully completed in schizophrenia and adjunctive use in major depressive disorder, with the US FDA approval obtained for these uses; Phase III studies in Alzheimer's disease and post-traumatic stress disorder are ongoing.
Copy number variations (CNV) involving multiple genes are ideal models to study polygenic neuropsychiatric disorders. Since 22q11.2 deletion is regarded as the most important single genetic risk ...factor for developing schizophrenia, characterizing the effects of this CNV on neural networks offers a unique avenue towards delineating polygenic interactions conferring risk for the disorder. We used a Df(h22q11)/+ mouse model of human 22q11.2 deletion to dissect gene expression patterns that would spatially overlap with differential resting-state functional connectivity (FC) patterns in this model (N = 12 Df(h22q11)/+ mice, N = 10 littermate controls). To confirm the translational relevance of our findings, we analyzed tissue samples from schizophrenia patients and healthy controls using machine learning to explore whether identified genes were co-expressed in humans. Additionally, we employed the STRING protein-protein interaction database to identify potential interactions between genes spatially associated with hypo- or hyper-FC. We found significant associations between differential resting-state connectivity and spatial gene expression patterns for both hypo- and hyper-FC. Two genes, Comt and Trmt2a, were consistently over-expressed across all networks. An analysis of human datasets pointed to a disrupted co-expression of these two genes in the brain in schizophrenia patients, but not in healthy controls. Our findings suggest that COMT and TRMT2A form a core genetic component implicated in differential resting-state connectivity patterns in the 22q11.2 deletion. A disruption of their co-expression in schizophrenia patients points out a prospective cause for the aberrance of brain networks communication in 22q11.2 deletion syndrome on a molecular level.
The Innovative Medicines Initiative is Europe's largest public-private initiative aiming to speed up the development of better and safer medicines for patients and nowhere is the need more urgent ...than in the area of CNS medications (2015a). NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) is one of the earliest IMI (2015b).
It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test ...the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.
The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.
No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.
Two enantiomeric series of milnacipran analogs have been synthesized and their effects on 5-HT, NE, and DA uptake inhibition have been measured.
A series of Milnacipran analogs with variation in the ...aromatic moiety were prepared in high enantiomeric excess. Structure–activity relationships for two parallel enantiomeric series are described. The (−)-(1
R,2
S)-naphthyl analog (
8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.
Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of β-amyloid peptide (Aβ) which is the main component of plaques found in AD brains and which cause memory impairment in ...mice. Therefore, there has been a major focus on the development of inhibitors of the Aβ producing enzymes γ-secretase and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Aβ-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized γ-secretase inhibitor LY450139. We sampled interstitial fluid Aβ from awake APPswe/PS1dE9 AD mice by in vivo Aβ microdialysis. In addition, we measured levels of endogenous brain Aβ extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Aβ-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Aβ in both in vivo models, we were unable to show any Aβ-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC₅₀ value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Aβ and wildtype cortical Aβ was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Aβ40 levels, compared with γ-secretase inhibition by LY450139.
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