China
Africa
Explore chapters and articles related to this topic
Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The purpose of cholinergic receptors (autoreceptors) present at the terminal of the presynaptic nerve is to provide a means of local control over nerve transmission. The binding of acetylcholine to the autoreceptor has the effect of inhibiting further release of acetylcholine. Also, the presynaptic nerve contains noradrenaline, which serves as another system of presynaptic control of acetylcholine release. Noradrenaline is released when the sympathetic nervous system is active and binds to those receptors in the cholinergic synapse and has the effect of inhibiting the release of acetylcholine. If derangements occur, where there is an insufficient release of acetylcholine, it would be logical for medicinal chemists to develop an agonist for the cholinergic receptor. While acetylcholine can be readily synthesised in the laboratory, it is not feasible as a treatment due to being hydrolysed in the stomach and blood and there is no selectivity of action. Hence, analogues of acetylcholine must be developed that are stable to hydrolysis and selective where they act in the body.
Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Ca2+ influx is influenced by the inherent properties of Ca2+ channels, and by the extracellular Ca2+ concentration – the larger this concentration the larger the influx, and conversely. Ca2+ influx is also influenced by the number of metabotropic receptors in the presynaptic terminal. Activation of these receptors affects, through second messengers, Ca2+ channels and both voltage-dependent and voltage-independent K+ channels in the presynaptic terminal. Inactivation of some K+ channels causes broadening of the AP, which increases Ca2+ influx, whereas gradual activation of a Ca2+-dependent K+ current reduces the amplitude of the AP, or its duration, or causes its failure altogether, which reduces Ca2+ influx. Some of these metabotropic receptors are autoreceptors, that is, they are receptors of the presynaptic membrane that are activated by neurotransmitters released from the same presynaptic terminal. Examples of such neurotransmitters are GABA and ATP. The activation of autoreceptors is a negative feedback mechanism that reduces Ca2+ influx and hence the release of neurotransmitters. The depression of transmission through autoreceptors is termed homosynaptic inhibition. The presynaptic metabotropic receptors could also be activated by neurotransmitters released into the extracellular space by other neurons in which case the inhibition is termed heterosynaptic inhibition.
Arvid Carlsson (1923–2018)
Published in Andrew P. Wickens, Key Thinkers in Neuroscience, 2018
Two other discoveries by Carlsson must also be briefly mentioned. First, in the late 1960s, Carlsson showed that tricyclic antidepressants not only blocked the reuptake of NA (as had been shown by Axelrod) but also of 5-HT as well. This would lead him to develop the first 5-HT uptake inhibitor called Zimelidine, which became the forerunner of many more selective 5-HT uptake blockers such as fluoxetine (Prozac) developed by the drug company Eli Lilly. Second, in the early 1970s, pharmacological research began to point to the possibility of receptors located on the presynaptic endings of catecholamine neurons that acted to regulate the release of their own neurotransmitters. Carlsson supported this theory by showing that the synthesis of dopamine was inhibited by certain dopaminergic receptor agonists and stimulated by antagonists. In 1975, Carlsson used the term autoreceptors to refer to this specialised presynaptic receptor – a word that has now become widely adopted. It is also now recognised that changes in autoreceptor function play a particularly significant role in the pharmacological action of many antidepressant drugs.
Designing multi-target drugs for the treatment of major depressive disorder
Published in Expert Opinion on Drug Discovery, 2023
Amit Kumar Halder, Soumya Mitra, Maria Natalia D. S. Cordeiro
Dopamine-2 (D2) receptors are present in postsynaptic dopaminergic target neurons and these also act pre-synaptically as autoreceptors. The D2 receptors are associated with Go and Gi proteins that inactivate adenylyl cyclase, decreasing cytosolic cAMP levels. Binding of DA to D2-like receptors inhibits the cAMP/PKA signaling pathway, ultimately affecting the CREB phosphorylation [60]. Olanzapine, a D2 receptor antagonist, demonstrates a much stronger antidepressant effect in combination with Fluoxetine [53,54]. Additionally, aripiprazole acts as a partial agonist of D2 and 5-HT1A receptors and at the same time, it is a 5-HT2A receptor antagonist [61]. Several investigations depicted that D2 receptor partial agonists are indeed useful adjuncts for the treatment of MDD since these significantly improve the efficacy of selective SSRIs [61–63]. Additionally, drugs like buspirone, aripiprazole, ipsapirone, and brexpiprazole may be categorized as dual 5-HT1A/D2 ligands [64]. Nevertheless, the rationale behind the benefit of combining the effects of these two receptors are not well understood. However, it is observed that it is the balance between the properties of these two receptors that may have a profound influence on the pathophysiology of depression. In addition, these two receptors may form constitutive heterodimers, the bio-functional mechanism of which is different from each protein [65].
Alpha-mangostin attenuates the apoptotic pathway of abamectin in the fetal rats’ brain by targeting pro-oxidant stimulus, catecholaminergic neurotransmitters, and transcriptional regulation of reelin and nestin
Published in Drug and Chemical Toxicology, 2022
Khairy A. Ibrahim, Mohammed Eleyan, Soad A. Khwanes, Rania A. Mohamed, Basim M. Ayesh
In this study, the declined contents of serotonin and dopamine in the fetal brain following prenatal intoxication with ABM may result from several factors, including the effects of ABM on the neurotransmitter biosynthesis, release, catabolism, storage, and receptor interaction. This suggestion is confirmed by a previous report which indicated that avermectins can indirectly inhibit the release of serotonin by inhibiting the release of glutamate via enhancement of gamma-aminobutyric acid release which suppresses the hypothalamic serotoninergic system (Moreira et al.2017). Furthermore, the decrease in dopamine level may be attributed to the stimulation of autoreceptors by avermectins which decreases the biosynthesis and/or release of dopamine (Rodrigues-Alves et al.2009). Moreover, abamectin and/or its metabolites may accumulate in the brain that leads to reduce serotonin and dopamine levels in the extracellular spaces of the brain and death of serotonergic and dopaminergic neurons by increasing the number of dormant receptors (Prichard et al.2012).
Evaluation of vilazodone for the treatment of depressive and anxiety disorders
Published in Expert Opinion on Pharmacotherapy, 2019
Mirella Stuivenga, Erik J. Giltay, Olivia Cools, Laurence Roosens, Hugo Neels, Bernard Sabbe
New treatment options are needed. The serotonin transporter and serotonin receptors are useful targets in the management of MDD and anxiety disorders. There are seven families of serotonin receptors, one of which is the 5-hydroxytryptamine-1 (5-HT1) subfamily of receptors (consisting of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F). The 5-HT1A receptor is the most widespread of all 5-HT receptors. The 5-HT1A receptors are metabotropic receptors, as these are not linked directly to ion channels, but act on ion channels through second messengers. The 5-HT1A receptors are coupled to intermediate molecules called G-proteins that affect second messengers through adenylyl cyclase and other pathways. The 5-HT1A receptors are located in the brain both as presynaptic autoreceptors and as heteroreceptors. The autoreceptors on the neurons in the raphe nuclei (located in the brain stem) inhibit the firing of these neurons. These autoreceptors thus dampen the increase of serotonin release initially when starting SSRI treatment. The 5-HT1A autoreceptor desensitization may take weeks. Postsynaptic heteroreceptors are found in the limbic system, hypothalamus, and frontal cortex (among others), affecting mood, cognition, and memory [8].