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Quantitative Changes in Receptor Concentrations as a Function of Disease
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2017
Interest in receptors in the heart stems from the possibility that changes in receptor properties of such receptors may explain cardiovascular abnormalities which result from metabolic disorders such as hyperthyroidism and diabetes. In addition, changes in receptor properties following myocardial infarction may be used to determine the extent of necrosis and the location of the infarct. If, as the result of ischemia there is a change in the receptor concentration, a radiopharmacon with high affinity for a heart receptor may provide an image of the infarct. Unlike studies with steroid hormone receptors where biopsy or tumor removal has provided a source of tissue for the determination of receptor content in man, most studies on receptors in the heart have used animal models. The receptor systems which have received most attention are the adrenergic receptor, both alpha- and beta-adrenergic, and the muscarinic acetylcholine receptor (m-AChR).
Efficacy, safety, and tolerability of ulotaront (SEP-363856, a trace amine-associated receptor 1 agonist) for the treatment of schizophrenia and other mental disorders: a systematic review of preclinical and clinical trials
Published in Expert Opinion on Investigational Drugs, 2023
Gia Han Le, Emily S. Gillissie, Taeho Greg Rhee, Bing Cao, Yazen Alnefeesi, Ziji Guo, Joshua D. Di Vincenzo, Muhammad Youshay Jawad, Andrew M. March, Ranuk Ramachandra, Leanna M.W. Lui, Roger S. McIntyre
Since antipsychotic use has been associated with numerous adverse effects, there has been an emerging consensus on the need for novel treatment strategies to treat the symptoms of schizophrenia spectrum disorder with enhanced efficacy and safety [24]. Focus has been redirected toward discovering and developing pharmacological agents that are non-D2 receptor-based, including treatments that are based on serotonergic, glutamatergic, ‘cholinergic, neuropeptidergic, hormone-based, other dopaminergic, metabolic, naturopathic, histaminergic, inflammation-based, and miscellaneous mechanisms’ [25]. For example, xanomeline is a muscarinic acetylcholine receptor M1/M4 agonist that has antipsychotic properties and is non-D2 receptor-based but has been associated with cholinergic adverse events [26,27]. In a double-blind, phase II clinical trial, Brannan et al. [27] administered trospium, a peripherally restricted muscarinic receptor antagonist, with xanomeline to patients with schizophrenia to reduce peripheral cholinergic effects of xanomeline and investigate the efficacy and safety of combining these agents for the treatment of schizophrenia. In a 5-week trial, a greater decrease in the Positive and Negative Syndrome Scale (PANSS) total score was observed in patients receiving xanomeline-trospium (−17.4 points) compared to the placebo (−5.9 points) (least-squares mean difference = −11.6 points; 95% CI, −16.1 to −7.1; p < 0.001) [27]. Despite reducing symptoms of schizophrenia, xanomeline-trospium was associated with cholinergic and anticholinergic adverse events [27].
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
The muscarinic acetylcholine receptor M4 is also known as the cholinergic receptor M4 (M4mAChR). The M4mAChR is widely present in CNS, particularly in the striatum. They regulate dopaminergic neurotransmission. Since M4mAChR is the negative regulator of dopamine release, increased dopamine levels in the striatum are associated with psychotic symptom psychosis, hyperkinetic movement disorders, and cognitive dysfunctions, such as schizophrenia and Parkinson’s and Alzheimer’s diseases. The drug xanomeline (LY-246708) has shown selective M1 and M4 receptor agonists, which showed promise for the treatment of Alzheimer’s disease and schizophrenia. Calhoun et al. have synthesized 2-azaspiro[3.4]octane [126] and 5-oxa-2-azaspiro[3.4]octane [127] derived oxadiazoles and related compounds 194 for selective modulation of M4mAChR (Figure 57). The in vitro (10−3 molar and 10−9 molar concentrations) and in vivo (0.1–500 mg/kg) studies revealed that these compounds are effective for psychotic depression, Alzheimer’s disease, schizoaffective disorder, Parkinson’s disease, bipolar disorder, post-traumatic stress disorder, and frontotemporal dementia.
Drug-induced myocardial dysfunction – recommendations for assessment in clinical and pre-clinical studies
Published in Expert Opinion on Drug Safety, 2020
Ahmad Ebrahimi, Joel S Raichlen, Amy Pointon, Christer Gottfridsson, Jiefen Munley, Paul Hockings, James Cartwright, Nicholas Buss, Johannes Wikström, Li-Ming Gan, Andrew Whittaker, Ali Khalil, Richard T George, Pavlo Garkaviy, David Brott
Pre-clinically, changes in cardiac contractility are typically used as a surrogate for cardiac dysfunction. There are a number of in vitro and in vivo techniques that can be applied to allow an integrated risk assessment of a decline in cardiac contractility either acutely or chronically. These assessments form part of a wider integrated preclinical cardiovascular safety strategy including the assessment of changes in ECG intervals, for example through the assessment of hERG inhibition related to QT prolongation, other hemodynamic parameters (heart rate and blood pressure) and changes in cardiac pathology, these additional areas are outside the scope of this review. The types of screens, assays, and models that can be used to detect and risk assess changes in cardiac contractility are illustrated in Figure 1. Early in discovery, when there is a significant chemical choice, in vitro molecular and cellular phenotypic screens are used as a means of hazard identification. The molecular screens provide coverage of receptors, enzymes, or ion channels relevant to cardiac contractility/dysfunction, for example, muscarinic acetylcholine receptor M2, L-type Ca2+ channel and cyclooxygenase 2. As these molecular screens do not cover all possible targets involved in modulation and control of cardiac contractility, this data can be supplemented with cellular phenotypic screens using human stem cell-derived cardiomyocytes or primary cardiomyocytes isolated from pre-clinical species, allowing further exploration of hazards in an intact cardiomyocyte both acute and chronically.