Showing papers by "ACADIA Pharmaceuticals Inc. published in 2013"
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TL;DR: It is hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson's disease (PD) at doses up to 100-fold lower than those effective in rodent cancer models.
Abstract: Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons. Nurr1 may be unable to bind ligands directly, but it forms heterodimers with other NucHRs that do. Using bioluminescence resonance energy transfer (BRET) assays to directly monitor interactions of Nurr1 with other NucHRs, we found the cancer drug bexarotene (Targretin, also LGD1069) displayed biased interactions with Nurr1-RXR heterodimers compared with RXR-RXR homodimers. Remarkably, at doses up to 100-fold lower than those effective in rodent cancer models, bexarotene rescued dopamine neurons and reversed behavioral deficits in 6-hydroxydopamine (6-OHDA) lesioned rats. Compared to the high doses used in cancer therapy, low doses of bexarotene have significantly milder side effects including a reduced increase in plasma triglycerides and less suppression of thyroid function. On the basis of extrapolations from rat to human doses, we hypothesize that low oral doses of bexarotene may provide an effective and tolerated therapy for Parkinson's disease (PD).
111 citations
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TL;DR: The shortened Scale for Assessment of Positive Symptoms for Parkinson's disease retains the reliability, sensitivity to change, and effect size of the larger scale while reducing administration time and, more importantly, score variability.
65 citations
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TL;DR: It is found that ACP-105 given alone decreases anxiety-like behavior and when ACp-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloids-β levels in the brain as well as improve cognition.
Abstract: Decreases of the sex steroids, testosterone and estrogen, are associated with increased risk of Alzheimer's disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer's disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), we administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. We assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. We found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer's disease warrants further investigation.
48 citations
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TL;DR: In male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186, so in addition to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacological profile compared to 17 β-ESTradiol in males.
Abstract: Drugs that selectively activate estrogen receptor β (ERβ) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERβ and ERα. The selective ERβ agonist AC-186 was evaluated in a rat model of Parkinson’s disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addition to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacological profile compared to 17β-estradiol in males.
29 citations
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TL;DR: The synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported for the first time.
25 citations
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26 Nov 2013TL;DR: Methods for the treatment of Parkinson's disease psychosis which comprise the administration of pimavanserin are described in this paper, where the authors describe the use of the drug as an effective treatment for the disease.
Abstract: Methods for the treatment of Parkinson's disease psychosis which comprise the administration of pimavanserin.
17 citations
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TL;DR: It is suggested that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.
Abstract: No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.
15 citations
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13 citations
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TL;DR: A new class of dihydrobenzofurans as potent and selective ERβ agonists and compound trans‐10‐SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the α‐ and β‐faces of the binding cavities of ERα and ERβ.
Abstract: Selective activation of the estrogen receptor (ER) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER and ER, occasionally causing severe side effects. cis-10-SR, was shown to have an EC50 value of <1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER/ER selectivity while still maintaining good potency (approximate to 10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ER at 10M. trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the - and -faces of the binding cavities of ER and ER beta.
10 citations
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30 Jan 2013TL;DR: Combinations of 5-HT2A inverse agonists or antagonists such as pimavanserin with antipsychotics such as risperidone are shown to induce a rapid onset of antipsychotic action and increase the number of responders when compared to therapy with the anti-psychotic alone.
Abstract: Combinations of 5-HT2A inverse agonists or antagonists such as pimavanserin with antipsychotics such as risperidone are shown to induce a rapid onset of antipsychotic action and increase the number of responders when compared to therapy with the antipsychotic alone. These effects can be achieved at a low dose of the antipsychotic, thereby reducing the incidence of side effects. The combinations are also effective at decreases the incidence of weight gain and increased glucose or prolactin levels caused by the antipsychotic.
7 citations
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TL;DR: The results suggest that F240S PAR2 receptors may be useful in screens to detect novel small-molecule PAR2 modulators and that further work on the biological importance of the F240s PAR2 variant is warranted.
Abstract: AC-55541 and AC-264613 are the first two small molecule agonists described for the G-protein-coupled receptor (GPCR) protease activated receptor 2 (PAR2), but whether they activate PAR2 through a similar mechanism as its tethered peptide ligand or soluble peptide mimetics of its tethered peptide ligand is unclear. Extracellular loop 2 (ECL2) has been shown to play a critical role in the activation mechanism of PAR2. Therefore, we constructed a series of PAR2 receptors mutated in ECL2, including a previously described polymorphic variant of PAR2 (F240S) and compared AC-55541 and AC-264613 to SLIGRL and a potent analogue of SLIGRL called 2-furoyl LGRLO in a series of functional assays including cellular proliferation, phosphatidyl inositol (PI) hydrolysis and beta-arrestin recruitment assays. Surprisingly receptors with the F240S mutation were constitutively active in all functional assays tested. Furthermore, AC-55541 and AC-264613 were potentiated over 30-fold at the receptors with the F240S mutation, whereas SLIGRL and 2-furoyl LGRLO were much less affected. In contrast, mutagenesis of charged residues in ECL2 confirmed their important role in the actions of peptide agonists of PAR2 whereas these mutations did not significantly affect activation of PAR2 by AC-55541 or AC-264613. These results suggest that F240S PAR2 receptors may be useful in screens to detect novel small molecule PAR2 modulators, and that further work on the biological importance of the F240S PAR2 variant is warranted.
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TL;DR: This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta.
Abstract: Selective estrogen receptor β (ERβ) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ERβ agonists, we focused on making an analogue of 16β,17α-estriol (16,17-epiestriol), a potent and one of the most ERβ selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos–Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2-diol (15). This A-CD analogue of 16β,17α-estriol is a highly selective (500-fold) ERβ full agonist over ERα with a pEC50 of 7.7 at ERβ. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the α-face, which might explain the high selectivity.
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TL;DR: This describes the syntheses of various dibenz ofurans and cycloheptanobenzofurans as estrogen receptor β agonists.
Abstract: This describes the syntheses of various dibenzofurans and cycloheptanobenzofurans as estrogen receptor β agonists.
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TL;DR: The results suggest that functional augmentation through 7TM receptor cross-talk is a rare event that may require specific conditions to occur.
Abstract: Background
Functional cross-talk between seven transmembrane (7TM) receptors can dramatically alter their pharmacological properties, both in vitro and in vivo. This represents an opportunity for the development of novel therapeutics that potentially target more specific biological effects while causing fewer adverse events. Although several studies convincingly have established the existence of 7TM receptor cross-talk, little is known about the frequencey and biological significance of this phenomenon.
Methodology/Principal Findings
To evaluate the extent of synergism in 7TM receptor signaling, we took a comprehensive approach and co-expressed 123 different 7TM receptors together with the angiotensin II type 1 receptor (AT1R) and analyzed how each receptor affected the angiotensin II (AngII) response. To monitor the effect we used integrative receptor activation/signaling assay called Receptor Selection and Amplification Technology (R-SAT). In this screen the thromboxane A2α receptor (TPαR) was the only receptor which significantly enhanced the AngII-mediated response. The TPαR-mediated enhancement of AngII signaling was significantly reduced when a signaling deficient receptor mutant (TPαR R130V) was co-expressed instead of the wild-type TPαR, and was completely blocked both by TPαR antagonists and COX inhibitors inhibiting formation of thromboxane A2 (TXA2).
Conclusions/Significance
We found a functional enhancement of AT1R only when co-expressed with TPαR, but not with 122 other 7TM receptors. In addition, the TPαR must be functionally active, indicating the AT1R enhancement is mediated by a paracrine mechanism. Since we only found one receptor enhancing AT1R potency, our results suggest that functional augmentation through 7TM receptor cross-talk is a rare event that may require specific conditions to occur.
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TL;DR: In this paper, the synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported.
Abstract: The synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported for the first time. The reaction results in high yields (51-94%) in combination with good ee (54-80%). Some of these products were subsequently recrystallized, affording enhanced optical purities (>99% ee).