Impact of increased alcohol consumption during the COVID-19-related lockdowns on admissions with liver disease, gastrointestinal bleeding and pancreatitis in Melbourne, Victoria.

This audit collates data on alcohol-related gastrointestinal (GI) admissions at Monash Health, Victoria, during the prolonged, coronavirus disease 2019 (COVID-19)-related lockdown July to October 2020 compared with the same periods in 2019 and 2021. We found a 58% increase in admissions in 2020 and a 16% increase in 2021, which also increased disproportionately to overall health service emergency presentations. Self-reported alcohol consumption increased by 2.

Time for Change: Stepping Up the FDA's Regulation of Dietary Supplements to Promote Consumer Safety and Awareness.

People are often looking for that quick fix when it comes to their health. With dietary supplements so readily available on the market, the public assume that they have been through rigorous testing. Dietary supplements are not tested as much as consumers believe.

Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity.

We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.

New approaches to the pharmacological treatment of obesity: can they break through the efficacy barrier?

In this review we assess the range of centrally active anorectics that are either in human clinical trials, or are likely to be so in the near future. We describe their weight loss efficacy, mode of action at both pharmacological and behavioural levels, where understood, together with the range of side effects that might be expected in clinical use. We have however evaluated these compounds against the considerably more rigorous criteria that are now being used by the Federal Drugs Agency and European Medicines Agency to decide approvals and market withdrawals.

Discovery and optimization of potent and selective functional antagonists of the human adenosine A2B receptor.

We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.

Discovery and functional evaluation of diverse novel human CB(1) receptor ligands.

Ligand-based virtual screening with a 3D pharmacophore led to the discovery of 30 novel, diverse and drug-like ligands of the human cannabinoid receptor 1 (hCB(1)). The pharmacophore was validated with a hit rate of 16%, binding selectivity versus hCB(2), and expected functional profiles. The discovered compounds provide new tools for exploring cannabinoid pharmacology.

Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas.

We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.

Discovery of a novel class of selective human CB1 inverse agonists.

Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.

Co-administration of SR141716 with peptide YY3-36 or oxyntomodulin has additive effects on food intake in mice.

Background: SR141716 has been shown to significantly inhibit food intake and reduce body weight by antagonizing CB(1) receptors. The gut hormones peptide YY(3-36) (PYY(3-36)) and oxyntomodulin (OXM) inhibit food intake through Y(2) and Glucagon-Like-Peptide (GLP)-1 receptors respectively.

Objective: To determine the effects of co-administration of SR141716 with either PYY(3-36) or OXM in mice on food intake.

5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice.

5-Hydroxytryptamine (5-HT)(2C) and 5-HT(1B) receptors are implicated in the inhibitory modulation of feeding behaviour. However, their respective, and possibly different, roles have not been clearly identified because of a lack of selective 5-HT(2C) receptor agonists. Here, using the putative, selective 5-HT(2C) receptor agonist VER23779, we show that its effects on feeding are fully reversed by pretreatment with a selective 5-HT(2C) receptor antagonist, but unaffected by pretreatment with either a 5-HT(1B) or a 5-HT(2A) receptor antagonist.

A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour.

Rationale: The cannabinoid CB(1) receptor inverse agonist SR141716A (rimonabant) is known to cause hypophagia and this study uses microstructural data to elucidate the relevant behavioural mechanisms.

Objectives: The aim of these studies was to determine the behavioural changes induced by SR141716A in animals consuming either a fat or carbohydrate solution. These behavioural changes were directly compared with those induced by behavioural manipulations that modify motivational state and palatability.

The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake.

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss.

Monoamine receptors in the regulation of feeding behaviour and energy balance.

We evaluate the likely utility of drugs that interact, either directly or indirectly, with monoamine binding receptors for the treatment of obesity. We discuss ligands at dopaminergic, adrenergic, serotoninergic and histaminergic receptors and also drugs that either release or inhibit the reuptake of monoamine neurotransmitters. We review evidence from preclinical studies of receptor distribution and function, together with the consequences of gene deletion in transgenic mouse strains and the results from human studies where these are available.

Serotonin 1B and 2C receptor interactions in the modulation of feeding behaviour in the mouse.

Rationale: To examine the functional relationship between 5-HT1B receptors (5-HT1B-R) and 5-HT2C receptors (5-HT2C-R) in the control of food intake.

Objectives: To compare the hypophagic effect of the 5-HT(2C/1B)-R agonist m-chlorophenylpiperazine (mCPP), with that of the selective 5-HT1B-R agonist CP-94,253 in both wildtype (WT) and 5-HT2C knockout (KO) mice.

Methods: The hypophagic effects of mCPP (1, 3 and 5.

Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists.

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported.

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

Cannabinoids and the regulation of ingestive behaviour.

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined.

Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors.

In the present study we compared the affinity of various drugs for the high affinity "agonist-preferring" binding site of human recombinant 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors stably expressed in monoclonal mammalian cell lines. To ensure that the "agonist-preferring" conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([3H]-ketanserin for 5-HT(2A) receptor and [3H]-mesulergine for 5-HT(2B) and 5-HT(2C) receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([125I]-DOI for 5-HT(2A) receptor binding and [3H]-5-HT for 5-HT(2B) and 5-HT(2C) receptor binding).

Tonic regulation of satiety by 5-HT receptors in the mouse: converging evidence from behavioural and c-fos immunoreactivity studies?

Activation of 5-HT(1B) receptors is thought to play an important role in the inhibitory influence of serotonin on feeding behaviour and body weight in mammals. Earlier studies have shown that 5-HT(1B)-knockout (KO) mice eat more and are heavier than wild-type (WT) controls and that the selective 5-HT(1B) receptor agonist CP-94,253 reduces food intake in food-deprived mice. Here we characterize the behavioural effects of both CP-94,253 and the selective 5-HT(1B) receptor antagonist SB224289 on feeding and other behaviours within the behavioural satiety sequence, and also report a c-fos mapping study using CP-94,253.

Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice.

Rationale: The possible role of compensatory changes in 5-HT2C receptors in the reduced hypophagic action of d-fenfluramine in 5-HT1B knockout (KO) mice was assessed by comparing their response to d-fenfluramine and the 5-HT2C receptor agonist mCPP. In addition we measured 5-HT(2C/A) receptor binding in 5-HT1B KO and wild-type (WT) mice and examined the effects of 5-HT1B receptor antagonists on d-fenfluramine-induced hypophagia in WT mice.

Methods: Hypophagic responses to d-fenfluramine (1-30 mg/kg) and mCPP (1-5.

Indoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported.

mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes.

The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist.