This article describes a set of 275 rules, developed over an 18-year period, used to identify compounds that may interfere with biological assays, allowing their removal from screening sets. Reasons ...for rejection include reactivity (e.g., acyl halides), interference with assay measurements (fluorescence, absorbance, quenching), activities that damage proteins (oxidizers, detergents), instability (e.g., latent aldehydes), and lack of druggability (e.g., compounds lacking both oxygen and nitrogen). The structural queries were profiled for frequency of occurrence in druglike and nondruglike compound sets and were extensively reviewed by a panel of experienced medicinal chemists. As a means of profiling the rules and as a filter in its own right, an index of biological promiscuity was developed. The 584 gene targets with screening data at Lilly were assigned to 17 subfamilies, and the number of subfamilies at which a compound was active was used as a promiscuity index. For certain compounds, promiscuous activity disappeared after sample repurification, indicating interference from occult contaminants. Because this type of interference is not amenable to substructure search, a “nuisance list” was developed to flag interfering compounds that passed the substructure rules.
Objective: Surgeons have no direct objective feedback on cochlear-implant electrode array (EA) positioning during insertion, yet optimal hearing outcomes are contingent on placing the EA as close as ...feasible to viable neural endings. This paper describes a system to non-invasively determine intracochlear positioning of an EA, without requiring any modifications to existing commercial EAs themselves. Methods: Electrical impedance has been suggested as a way to measure EA proximity to the inner wall of the cochlea that houses auditory nerve endings-the modiolus. In this paper, we extend prior work and demonstrate for the first time the relationship between bipolar access resistance and proximity of the EA to the modiolus (E-M proximity). We also evaluate two methods for producing direct, real-time estimates of E-M proximity from bipolar impedance measurements. Results: We show that bipolar access resistance is highly correlated with E-M proximity and can be approximately modeled by a power law function. This one dimensional model is shown to be capable of producing accurate real-time estimates of E-M proximity, but its simplicity also limits the potential for future improvement. To address this challenge, we propose a new prediction approach based on a recurrent neural network, which generated an overall prediction accuracy of 93.7%. Conclusion: Bipolar access resistance is highly correlated with E-M proximity, and can be used to estimate EA positioning. Significance: This work shows how impedance sensing can be used to localize an EA during insertion into the small, enclosed cochlear environment, without requiring any modifications to existing clinically used EAs.
In the development of telemanipulated surgical robots, a class of continuum robots known as concentric tube robots has drawn particular interest for clinical applications in which space is a major ...limitation. One such application is transnasal surgery, which is used to access surgical sites in the sinuses and at the skull base. Current techniques for performing these procedures require surgeons to maneuver multiple rigid tools through the narrow confines of the nasal passages, leaving them with limited dexterity at the surgical site. In this article, we present a complete robotic system for transnasal surgery featuring concentric tube manipulators. It illustrates a bagging concept for sterility, and intraoperatively interchangeable instruments that work in conjunction with it, which were developed with operating room workflow compatibility in mind. The system also includes a new modular, portable surgeon console, a variable view-angle endoscope to facilitate surgical field visualization, and custom motor control electronics. Furthermore, we demonstrate elastic instability avoidance for the first time on a physical prototype in a geometrically accurate surgical scenario, which facilitates use of higher curvature tubes than could otherwise be used safely in this application. From a surgical application perspective, this article presents the first robotic approach to removing tumors growing behind the eyes in the orbital apex region, which has not been attempted previously with a surgical robot.
DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all ...rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.
•The dopamine D1 potentiator DETQ was tested in humanized D1 mice and rhesus monkeys.•Actions of DETQ were dependent on endogenous dopaminergic tone.•DETQ displayed a behavioral profile consistent with central D1 receptor activation.•Neurochemical actions of DETQ support potential pro-cognitive effects.•D1 potentiators show promise for Parkinson's disease and other CNS disorders.
An amine-containing molecule called Compound A has been reported by a group from Bristol-Myers Squibb to act as a positive allosteric modulator (PAM) at the dopamine D1 receptor. We synthesized the ...more active enantiomer of Compound A (BMS-A1) and compared it with the D1 PAMs DETQ and MLS6585, which are known to bind to intracellular loop 2 and the extracellular portion of transmembrane helix 7, respectively. Results from D1/D5 chimeras indicated that PAM activity of BMS-A1 tracked with the presence of D1 sequence in the N-terminal/extracellular region of the D1 receptor, a unique location compared with either of the other PAMs. In pairwise combinations, BMS-A1 potentiated the small allo-agonist activity of each of the other PAMs, while the triple PAM combination (in the absence of dopamine) produced a cAMP response about 64% of the maximum produced by dopamine. Each of the pairwise PAM combinations produced a much larger leftward shift of the dopamine EC
than either single PAM alone. All three PAMs in combination produced a 1000-fold leftward shift of the dopamine curve. These results demonstrate the presence of three non-overlapping allosteric sites that cooperatively stabilize the same activated state of the human D1 receptor. SIGNIFICANCE STATEMENT: Deficiencies in dopamine D1 receptor activation are seen in Parkinson disease and other neuropsychiatric disorders. In this study, three positive allosteric modulators of the dopamine D1 receptor were found to bind to distinct and separate sites, interacting synergistically with each other and dopamine, with the triple combination causing a 1000-fold leftward shift of the response to dopamine. These results showcase multiple opportunities to modulate D1 tone and highlight new pharmacological approaches for allosteric modulation of G-protein-coupled receptors.
Background
Cochlear‐implant electrode arrays (EAs) are currently inserted with limited feedback, and impedance sensing has recently shown promise for EA localisation.
Methods
We investigate the use ...of impedance sensing to infer the progression of an EA during insertion.
Results
We show that the access resistance component of bipolar impedance sensing can detect when a straight EA reaches key anatomical locations in a plastic cochlea and when each electrode contact enters/exits the cochlea. We also demonstrate that dual‐sided electrode contacts can provide useful proximity information and show the real‐time relationship between impedance and wall proximity in a cadaveric cochlea for the first time.
Conclusion
The access resistance component of bipolar impedance sensing has high potential for estimating positioning information of EAs relative to anatomy during insertion. Main limitations of this work include using saline as a surrogate for human perilymph in ex vivo models and using only one type of EA.
Rationale
Dopamine (DA) signaling through the D1 receptor has been shown to be integral to multiple aspects of cognition, including the core process of working memory. The discovery of positive ...allosteric modulators (PAMs) of the D1 receptor has enabled treatment modalities that may have alternative benefits to orthosteric D1 agonists arising from a synergism of action with functional D1 receptor signaling.
Objectives
To investigate this potential, we have studied the effects of the novel D1 PAM DPTQ on a spatial delayed response working memory task in the rhesus monkey. Initial studies indicated that DPTQ binds to primate D1R with high affinity and selectivity and elevates spontaneous eye blink rate in rhesus monkeys in a dose-dependent manner consistent with plasma ligand exposures and central D1activation.
Results
Based on those results, DPTQ was tested at 2.5 mg/kg IM in the working memory task. No acute effect was observed 1 h after dosing, but performance was impaired 48 h later. Remarkably, this deficit was immediately followed by a significant enhancement in cognition over the next 3 days. In a second experiment in which DPTQ was administered on days 1 and 5, the early impairment was smaller and did not reach statistical significance, but statistically significant enhancement of performance was observed over the following week. Lower doses of 0.1 and 1.0 mg/kg were also capable of producing this protracted enhancement without inducing any transient impairment.
Conclusions
DPTQ exemplifies a class of D1PAMs that may be capable of providing long-term improvements in working memory.
The binding site for DETQ 2-(2,6-dichlorophenyl)-1-((1
,3
)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1
)-yl)ethan-1-one, a positive allosteric modulator (PAM) of ...the dopamine D1 receptor, was identified and compared with the binding site for CID 2886111
-(6-
-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide, a reference D1 PAM. From D1/D5 chimeras, the site responsible for potentiation by DETQ of the increase in cAMP in response to dopamine was narrowed down to the N-terminal intracellular quadrant of the receptor; arginine-130 in intracellular loop 2 (IC2) was then identified as a critical amino acid based on a human/rat species difference. Confirming the importance of IC2, a
2-adrenergic receptor construct in which the IC2 region was replaced with its D1 counterpart gained the ability to respond to DETQ. A homology model was built from the agonist-state
2-receptor structure, and DETQ was found to dock to a cleft created by IC2 and adjacent portions of transmembrane helices 3 and 4 (TM3 and TM4). When residues modeled as pointing into the cleft were mutated to alanine, large reductions in the potency of DETQ were found for Val119 and Trp123 (flanking the conserved DRY sequence in TM3), Arg130 (located in IC2), and Leu143 (TM4). The D1/D5 difference was found to reside in Ala139; changing this residue to methionine as in the D5 receptor reduced the potency of DETQ by approximately 1000-fold. None of these mutations affected the activity of CID 2886111, indicating that it binds to a different allosteric site. When combined, DETQ and CID 2886111 elicited a supra-additive response in the absence of dopamine, implying that both PAMs can bind to the D1 receptor simultaneously.
Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the ...vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 μg, 20 μg, 2 mg/kg or vehicle. When tested 90–120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.
The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted ...U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), which is currently the only D1 PAM for which published in vivo data is available. In vitro studies showed selective potentiation of the human D1 receptor without significant allosteric agonist effects. Due to a species difference in affinity for DETQ, transgenic mice expressing the human D1 receptor (hD1 mice) were used in vivo. In contrast to D1 agonists, DETQ increased locomotor activity over a wide dose-range without inverted U-shaped dose response or tachyphylaxis. DETQ also reversed hypo-activity in mice with dopamine depletion due to reserpine pretreatment, suggesting potential for treatment of motor symptoms in Parkinson's disease. Potential pro-cognitive effects were supported by improved performance in the novel object recognition task, enhanced release of cortical acetylcholine and histamine, and increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB. In addition, DETQ enhanced wakefulness in EEG studies and decreased immobility in the forced-swim test. Together, these results provide support for potential utility of D1 PAMs in the treatment of several neuropsychiatric disorders. LY3154207, a close analog of DETQ, is currently in phase 2 clinical trials.
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