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Behavioural pharmacology
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
The behavioural pharmacology of inverse ago-nists at the benzodiazepine binding site is the mirror image of that of full agonists. Thus, these compounds are convulsant, anxiogenic and produce behavioural arousal. Compounds exist of differing efficacies in which these pharmacological properties are more or less present. Although inverse agonists have been described in several chemical families, it is the β-carboline inverse agonists that have received the most attention, and, in particular, the full inverse agonist DMCM (Petersen, 1983) and the partial inverse agonist FG 7142. In addition to their own intrinsic pharmacological activity, inverse agonists will also, of course, potently reverse the effects of benzodiazepine full agonists (Oakley and Jones, 1980; Tenen and Hirsch, 1980; Cowen et al, 1981).
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
To encompass the full range of drug actions at the DARs, an updated drug definition was proposed [63]. According to this terminology, an agonist is defined as a substance that binds to a specific receptor and stimulates the signaling pathway known to be associated with it. A partial agonist causes a less than maximal response but can also act as a partial antagonist. An antagonist has no effects on its own but, rather, blocks an agonist-induced signaling. A somewhat confusing term is inverse agonist, defined as a ligand that binds to a receptor and inhibits agonist-independent (constitutive) signaling. These concepts are schematically presented in Figure 2.11.
Antiepileptic Actions of Benzodiazepines
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
A climate of optimism and excitement is currently present in the field of benzodiazepine pharmacology, as discussed below. This is because of the potential for new drugs that have more suitable clinical profiles. The benzodiazepine receptor spectrum indicates that partial agonists and partial inverse agonists exist, and others are being developed. These compounds will hopefully provide anticonvulsant efficacy with reasonable pharmacokinetics, but also with fewer side effects. These include sedation, muscle relaxation, amnesia, and ethanol potentiation; less tolerance development is another desirable feature being sought. Some success appears to have been obtained with new experimental benzodiazepine receptor drugs.90-92 Partial agonist character may explain the more desirable profile for these and potential other new drugs. Partial agonists also may be used as antidotes for overdoses of full agonists or full inverse agonists but which do not totally lack the desired clinical activity. Of course, the spectrum of drug action may actually be due, at least partially, to the existence of distinct receptor subtypes, but either explanation is potentially useful clinically.
Novel therapeutic and drug development strategies for tobacco use disorder: endocannabinoid modulation
Published in Expert Opinion on Drug Discovery, 2020
Arguably one of the most promising candidates for smoking cessation in recent years was rimonabant, an anti-obesity drug and inverse agonist at the cannabinoid (CB) receptor 1. Indeed, abstinence at the end of 10 weeks of treatment with rimonabant (20 mg/day) and at 48 weeks follow-up was higher than placebo in a pooled analysis of three randomized double-blind controlled trials [17]. However, the high rate of psychiatric side effects, notably the induction of anxiety and depression and risk of emergence of suicidal ideation [18], led to the voluntary withdrawal of rimonabant from the European market in 2008 [19]. Nevertheless, there is an increasing understanding of the role of the endocannabinoid system in reward processing and addiction [20,21] suggesting that there may still be potential tobacco smoking cessation candidates found that work via endocannabinoid modulation.
Beta-blockers in asthma: myth and reality
Published in Expert Review of Respiratory Medicine, 2019
Angelica Tiotiu, Plamena Novakova, Krzysztof Kowal, Alexander Emelyanov, Herberto Chong-Neto, Silviya Novakova, Marina Labor
According to the affinity for the active/inactive receptor status, the ligands are classified by agonists, antagonists, partial and inverse agonists. Full agonists might move the equilibrium in the direction of active form and lead to a cellular response [2]. For example, the endogenous ligand for the β2-adrenoceptor, epinephrine, and agonists used in asthma like salmeterol and formoterol activate both pathways [8]. Partial agonists stabilize the active conformation of the receptor as a full agonist, although less frequently [21]. Inverse agonists have more affinity for the inactive state and antagonists block the effects of both agonists and inverse agonists [2]. For example, alprenolol is a partial agonist at both pathways while carvedilol and propranolol are inverse agonists at G-cAMP pathway but partial agonists of ERK pathway [24]. Nadolol is an inverse agonist at both pathways having proved several beneficial effects in asthma, even though there are currently no large-scale trials to confirm these results [2]. In contrast with carvedilol and propranolol, nadolol reduces AHR probably in rapport with its effect on the arrestin/ERK pathway, in line with the hypothesis of a possible detrimental role of this signaling in asthma [8,10,22,23,25–27].
A patent update on cannabinoid receptor 1 antagonists (2015-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
George Amato, Nayaab S Khan, Rangan Maitra
Pyrazoles, similar to 1, are claimed in patent activity by the Beijing Institute et al. [19]. The focus is on 1,5-diaryl-4-methyl pyrazoles with a urea in the three position, as exemplified by compound 3 (Figure 2). Compound 3 and several others were shown to be peripherally restricted using pharmacokinetic (PK) studies in rodents. In vivo efficacy data were not provided in the patent, but 3 is the subject of a 2017 publication[10]. Compound 3, designated TXX-522 in the paper, was shown to be an orally bioavailable neutral antagonist which reduced body weight gain and improved insulin resistance in a diet induced obesity (DIO) mouse model of metabolic syndrome. It was noted that food intake was not reduced by this compound. Centrally acting inverse agonists often reduce food intake.