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Functional characterisation of the GABAA receptors
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
In the case of the modulatory sites of the GABAA receptor care must be taken in the comparison of the efficacy determinations from different laboratories. Some investigators choose to determine efficacy at the EC10 for GABA achvation in which case the maximum effect of the positive allosteric modulators is numerically large. However, others carry out the determinations at GABA EC50, where both negative and positive modulation can be quantified with facility. Clearly, measurement of efficacy at multiple receptor subtypes, with a single compound, also requires the determination of agonist concentration-response curves for each receptor subtype. These procedures are time consuming and rigorous comparisons are rarely possible with the data that are currently available in the public domain.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
There is another major class of drugs that act as positive allosteric modulators of the GABAA chloride channel. These are the barbiturates, such as phenobarbital, pentobarbital, and secobarbital. The barbiturates are also widely used as hypnotic agents (sleeping pills) and as adjuncts to anesthetics during surgery. Moreover, some barbiturates find important use as antiepileptic drugs (e.g., phenobarbital and primidone [Mysoline®]). Importantly, barbiturates bind to a different site on the chloride channel than do the benzodiazepines, and they increase the duration of chloride channel open time (prolonging inhibition) rather than the frequency of channel opening.
Paper 5 Answers
Published in James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal, Get Through, 2014
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal
Many drugs act by altering enzyme function. Positive allosteric modulation of an enzyme by a drug may be either direct or indirect. Direct positive allosteric modulation occurs when the rate of the enzyme reaction and the affinity for its substrate are increased directly (e.g. insulin acting on tyrosine kinase). Indirect positive allosteric modulation occurs where the drug acts through a series of reactions to modulate the enzyme’s activity (e.g. adrenaline is an indirect positive allosteric modulator of adenylyl cyclase by acting at the β-adrenoceptor).
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
However, despite the advantages of allosteric drugs over orthosteric ligands above mentioned, classical allosteric modulation is not the perfect solution for new drug discovery, as there are lots of chemical and pharmacological aspects that must be considered when developing allosteric drugs. For example, the low evolutionary pressure on allosteric sites can generate huge differences between species. Second, the requirement of the presence of the endogenous agonist could also limit the efficacy of PAMs and NAMs; in fact, this state dependence of allosteric modulators must be reconsidered in degenerative pathologies in which there is a progressive loss of endogenous orthosteric tone. Third, signal bias generated by allosteric modulators (i.e. BAMs) may cause unwanted and/or unpredicted physiological effects that must be taken into account, and fourth, allosteric modulators could activate simultaneously both homo- and heterodimers of the target receptor, which may alter the physiological response [170]. However, this last disadvantage could be overcome, for example, by the use of heteromer-selective modulators [40]. Several chemical complications also appear in the allosteric drug design derived from a very shallow structure–activity relationship, difficulty of integrating polar and solubilizing groups, and the presence of molecular switches, which can undergo subtle structural changes that can lead to PAM, NAM, or SAM behavior [170].
Selective α7 nicotinic receptor agonists and positive allosteric modulators for the treatment of schizophrenia – a review
Published in Expert Opinion on Investigational Drugs, 2020
Kirsten Antonio-Tolentino, Corey R. Hopkins
Despite significant efforts in the discovery of novel α7 nAChR partial agonists, there has been no approvals for those agents in development for cognitive improvement in schizophrenia patients. Many agents have advanced to clinical trials, however, they have all been discontinued for a multitude of reasons [45], for example, lack of efficacy and further toxicity concerns have arisen for EVP-6124. Future efforts may find success in novel positive allosteric modulators. However, the overall drug discovery landscape for psychiatric disorders is uncertain because many large pharmaceutical companies have left this field and hence these actions put an onus on small biotech, government agencies, and academic laboratories to help fill this gap. Furthermore, future clinical studies may require more considered designs to overcome the large placebo effect that is seen in SZ clinical trials. There remains hope for new therapies in this area; however, it is not an area that will be overpopulated going forward.
Has the bloom gone out of lorcaserin following the CAMELLIA-TIMI61 trial?
Published in Expert Opinion on Pharmacotherapy, 2021
In addition to the development of new and more specific 5-HT2c receptor agonists, there is also the strategy of allosteric modulation of receptor activation. The 5-HT2c receptor has been shown to have extracellular allosteric sites that can positively modulate activation in response to agonist binding. Several drugs and natural molecules have been shown to confer positive allosteric modulation, as reviewed recently [20]. One compound (N-[(1-benzyl1H-indol-3-yl)methyl]pyridin-3-amine) was shown to achieve higher concentrations in brain tissue compared to plasma in rats and reduce body weight and food intake [21].Thus, an exciting path forward is to explore the use of positive allosteric modulators, either independently or in combination with lower doses of selective 5-HT2c agonists.