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Benzodiazepines as anxiolytics
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Finally, the possibility of an endogenous ligand or endozepine needs to be considered (the concept and evidence for such compounds is given later in this chapter). Such a substance would reduce the binding of the flumazenil tracer to the receptor and provide the picture described. However, this substance could not be an inverse agonist causing panic as flumazenil would have blocked it and so been anxiolytic not anxiogenic. However, it is possible that an endogenous agonist exists, possibly as a compensatory mechanism, and the anxiogenic effects of flumazenil are due to its displacing this from the receptor so precipitating a type of withdrawal anxiety. If an endogenous agonist exists, it can only be present in panic patients (and possibly GAD) as the controls did not get anxious.
How can we improve the measurement of receptor signaling bias?
Published in Expert Opinion on Drug Discovery, 2023
While quantifying bias using the same cellular system, system bias will equally affect all the tested ligands and could therefore be eliminated by quantifying bias relative to a reference ligand. Ideally, the endogenous agonist is used as a reference ligand to check how drug candidates differ from the natural signaling. Otherwise, a ligand with very similar signaling through different pathways (balanced), is used as reference. Definitely, a ligand referred to as ‘balanced’ might become ‘biased’ if tested in another system or assay. Likewise, a tested ligand may be unbiased, relative to the reference ligand, in one particular pathway but biased in another. Hence, designations such as ‘biased’ or ‘balanced’ cannot be used as an absolute descriptor for a ligand, but should be reported and interpreted in the context of a specific receptor, reference ligand, and/or pathways.
Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease
Published in Stress, 2019
Aki T-B. Chaffin, Yanbin Fang, Karlton R. Larson, Joram D. Mul, Karen K. Ryan
The MC4R is a G protein-coupled receptor expressed widely in the adult central nervous system (Cone, 2005; Tao, 2010). Its activity is coordinated by opposing actions of its endogenous agonist, αMSH, and its endogenous antagonist, agouti-related protein (AgRP) (Fong et al., 1997; Ollmann et al., 1997; Shutter et al., 1997). In addition, the receptor has intrinsic constitutive activity on which AgRP can act as an inverse agonist (Srinivasan et al., 2004). αMSH producing neurons in the arcuate nucleus of the hypothalamus are activated by restraint stress (Liu et al., 2007) and provide melanocortinergic input to MC4R-expressing neurons in key stress and feeding-regulatory brain regions including the paraventricular nucleus of the hypothalamus (PVN), the medial amygdala (MeA), and the nucleus accumbens (NAc) (Balthasar, 2006; Wang et al., 2015). Activation of MC4Rs by αMSH or pharmacological agonists acutely stimulates the HPA axis in male rats and mice (Liu et al., 2013) and induces weight loss by reducing caloric intake and increasing energy expenditure in both sexes (Fan et al., 1997; Hamilton & Doods, 2002). Conversely, loss of MC4R function (Ryan et al., 2014) or its pharmacological blockade (Kokare et al., 2010; Liu et al., 2007; Serova et al., 2013) blunts acute restraint stress-induced corticosterone elevation in male rats and mice. MC4R loss-of-function also induces weight gain by increasing caloric intake and decreasing energy expenditure in both sexes (Huszar et al., 1997). Our results (Figure 4) are consistent with these reports.
Host–microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling
Published in Gut Microbes, 2020
Ning Ma, Ting He, Lee J. Johnston, Xi Ma
Serotonin is an endogenous agonist of human AhR.61 Abnormal serotonin metabolism within the gut correlates to gastrointestinal diseases, such as irritable bowel syndrome.62 In addition to serotonin itself, its catabolites, such as 5-HIAA, are potential AhR ligands.63 Melatonin has been reported to modulate a number of physiological functions, notably circadian rhythm, free radical scavenging, and oxidation resistance.64 However, whether melatonin can directly act as an AhR ligand remains to be elucidated.