PQCA
目录号 : GC63153
PQCA 是一种高度选择性且有效的毒蕈碱 M1 受体阳性变构调节剂。PQCA 在恒河猴和人 M1 受体上的 EC50 值分别为 49 nM 和 135 nM，并对其他毒蕈碱受体无活性。PQCA 具有减少与阿尔茨海默氏病相关的认知缺陷的潜力。
Cas No.:1144504-35-7
Sample solution is provided at 25 µL, 10mM.
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PQCA is a highly selective and potent muscarinic M1 receptor positive allosteric modulator. PQCA has an EC50 value of 49 nM and 135 nM on rhesus and human M1 receptor, respectively. PQCA is inactive for other muscarinic receptors. PQCA has potential to reduce the cognitive deficits associated with Alzheimer’s disease[1][2].
PQCA (3-30 mg/kg; oral administration; single- or pair-housed male rhesus monkeys) treatment attenuates the scopolamine deficits in PAL and CPT tasks. Blockade of muscarinic signaling by scopolamine produces significant impairments in both tasks[1].
[1]. Lange HS, et al. The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys. J Pharmacol Exp Ther. 2015 Dec;355(3):442-50.
[2]. Uslaner JM, et al. The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque. Psychopharmacology (Berl). 2013 Jan;225(1):21-30.
| Cas No. | 1144504-35-7 | SDF | |
| 分子式 | C22H20N4O3 | 分子量 | 388.42 |
| 溶解度 | DMSO : 10 mg/mL (25.75 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5745 mL | 12.8727 mL | 25.7453 mL |
| 5 mM | 0.5149 mL | 2.5745 mL | 5.1491 mL |
| 10 mM | 0.2575 mL | 1.2873 mL | 2.5745 mL |
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The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model
Behav Brain Res 2015;287:96-9.PMID:25800972DOI:10.1016/j.bbr.2015.03.029.
We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aβ were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.
Sterically demanding pyridine-quinoline anchoring ligands as building blocks for copper(I)-based dye-sensitized solar cell (DSSC) complexes
Dalton Trans 2022 Oct 11;51(39):15049-15066.PMID:36112091DOI:10.1039/d2dt02382b.
The Pfitzinger condensation reaction was employed to synthesise N^N sterically demanding ligands bearing carboxylic acid anchoring groups, namely 2,2'-pyridyl-quinoline-4-carboxylic acid (PQCA), 6'-methyl-2,2'-pyridyl-quinoline-4-carboxylic acid (6'-Mepqca), 8-methyl-2,2'-pyridyl-quinoline-4-carboxylic acid (8-Mepqca) and 8,6'-dimethyl-2,2'-pyridyl-quinoline-4-carboxylic acid (8,6'-Me2pqca). Preparation of the methyl ester analogues 6'-Mepqcame, 8-Mepqcame and 8,6'-Me2pqcame is also described. All ligands were fully characterised including the X-ray structures of PQCA, 6'-Mepqca and 8-Mepqca. We also describe the synthesis and characterisation of seven homoleptic copper(I) complexes of the formula [Cu(N^N)2][PF6] (N^N = PQCA (1), 6'-Mepqca (2), 8-Mepqca (3), 8,6'-Me2pqca (4), 6'-Mepqcame (6), 8-Mepqcame (7) and 8,6'-Me2pqcame (8)). Characterisation of the copper(I) complexes includes FT-IR, elemental analyses, multinuclear NMR spectroscopy, UV-vis spectroscopy, cyclic voltammetry, and a single-crystal X-ray diffraction study. The molecular structures of 1·DMSO, 2{2·Me2CO·0.5H2O}, 4, 6·CHCl3·0.13H2O, 2{7·C5H12}·CHCl3 and 8 have been determined, revealing that these complexes adopt a distorted tetrahedral geometry. These are the first crystallographically characterised examples of copper(I)-based coordination compounds incorporating the above mentioned N^N pyridyl-quinoline ligands. In solution, the new complexes are purple to red colored, while 2 displayed excellent stability in acetone at ambient temperature over a month. The absorption spectra of 1-8 display a main broad MLCT band with values of λmax at ∼530 nm and ε values ranging from 1800 to approximately 10 000 dm3 mol-1 cm-1. The photovoltaic performance of the prepared compounds was evaluated on mesoporous nanocrystalline TiO2 dye-sensitized solar cells (DSSCs), and compared with that of the [Cu(dmdcbpy)2][PF6] dye (dmdcbpy = 6,6'-dimethyl-2,2'-bipyridine-4,4'-dicarboxylic acid) (5), that has been used as standard, under the same experimental conditions. From a combination of electrochemical and absorption spectroscopy experiments, the MLCT energy levels of 2 are appropriate for electron injection onto the titania conduction band. Upon optimisation of the semiconductor's architecture, 2 proved to be the most efficient dye, reaching a conversion efficiency of η = 1.20%, which is slightly higher than that of 5 (η = 1.05%), mainly attributed to higher Voc values.
The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys
J Pharmacol Exp Ther 2015 Dec;355(3):442-50.PMID:26446308DOI:10.1124/jpet.115.226712.
Improved treatment of Alzheimer disease (AD) is a significant unmet medical need that is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by gastrointestinal side effects owing to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA (1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4 H-quinolizine-3-carboxylic acid) has been demonstrated to improve cognition in a variety of rodent and nonhuman primate cognition models without producing significant gastrointestinal side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in nonhuman primates: paired-associates learning (PAL) and the continuous-performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of subeffective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1-positive allosteric modulators, either as monotherapy or as an add-on to current standards of care, have potential to reduce the cognitive deficits associated with AD.
The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque
Psychopharmacology (Berl) 2013 Jan;225(1):21-30.PMID:22825578DOI:10.1007/s00213-012-2788-8.
Rationale: The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects. Objectives: Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. Results: PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies. Conclusions: These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.
Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey
Psychopharmacology (Berl) 2015 Jun;232(11):1859-66.PMID:25491927DOI:10.1007/s00213-014-3813-x.
Rationale: The standards of care for Alzheimer's disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated. Methods: We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window. Results: All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range. Conclusions: These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer's disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.