The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to ...treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzohquinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-1,4'-bipiperidine-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators.
Abstract Background Patients undergoing palliative surgeries for single-ventricle conditions are affected by multiple comorbidities or non-cardiac conditions. The prevalence, costs and the cost ...implications of these conditions have not been assessed. Methods Administrative costing records from four hospitals in Australia and New Zealand were linked with the Fontan registry database to analyze the inpatient resource use for co-morbid or non-cardiac conditions. Inpatient costing records from the birth year through to Fontan completion were available for 156 patients. The most frequent primary diagnoses were hypoplastic left heart syndrome (33%), double inlet left ventricle (13%), and tricuspid atresia (12%). Results During the staged surgical treatment period, children had a mean of 10 ± 6 inpatient admissions and spent 85 ± 64 days in hospital. Among these admissions, 3 ± 5 were for non-cardiac conditions, totaling 21 ± 41 inpatient days. Whilst cardiac surgeries were the major reason for resource use (77% of the total cost), other cardiac care that is not surgical contributed 5% and non-cardiac admissions 18% of the total cost. The three most prevalent non-cardiac diagnostic admission categories were ‘Respiratory system’, ‘Digestive system’, and ‘Ear, nose, mouth and throat’, affecting 28%, 21% and 34% of the patients respectively. Multivariate regression estimated that admissions for each of these categories resulted in an increased cost of $34,563 ( P = 0.08), $52,438 ( P = 0.05) and $10,525 ( P = 0.53) per patient respectively for the staged surgical treatment period. Conclusions Non-cardiac admissions for single-ventricle patients are common and have substantial resource implications. Further research assessing the causes of admission and extent to which admissions are preventable is warranted.
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Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs ...is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
Triazolopyridine ethers with mGlu
positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The ...effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu
PAMs for the treatment of schizophrenia and merit further preclinical investigation.
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