No abstract

Single crystal X-ray structures of methanol solvates of trimesic acid provide an insight into the step-wise dis-assembly of this strongly hydrogen-bonded acid through the disruption of acidacid head-to-tail dimer motifs by alcohols.Trimesic acid (benzene-1,3,5-tricarboxylic acid, H 3 TMA) is amongst the most used members of the benzenepolycarboxylic acid family, favoured by the supramolecular chemist for their numerous divergent carboxyl groups, useful in the creation of extensive arrays through hydrogen bonding 1 and metal-coordination bonds. 2 The inclusion of solvent molecules into the "chicken wire" solid state structure of H 3 TMA 1a,3 received interest, notably from Herbstein, in the 1970s and 1980s, 1a,1c,4 with more recent work investigating the formation of channels in H 3 TMA solvates utilising polyaromatic compounds as templates. 5 While the crystallographic study of solvates was initially hindered by rapid desolvation at room temperature, 6 the advent of low temperature systems for Xray data collection now allows for more precise structural determinations. 4e The crystallisation of a methanolic solution of H 3 TMA over a period of seven days at 218 °C resulted in a mixture of colourless blocks H 3 TMA·MeOH, 1, and colourless needles H 3 TMA·2MeOH, 2, the latter being the major component. Both 1 and 2 were analysed using single-crystal X-ray diffraction † and were found to possess tape structures, maintained by strong O-H…O hydrogen bonding interactions. 7

1. The actions of the beta-adrenoceptor agonist isoprenaline on glucose and glycogen metabolism, in the presence of various concentrations of insulin, were investigated in isolated soleus muscle preparations taken from eu-, hyper- and hypothyroid rats. 2. Hyperthyroidism, induced by 3,3',5-tri-iodo-D-thyronine (T3) administration for 5 days, increased the rate of lactate formation and suppressed the rate of glycogen synthesis in soleus muscle in response to isoprenaline, even in the presence of physiological or supraphysiological insulin concentrations. 3. Hypothyroidism, induced by administration of 6-n-propyl-2-thiouracil for 4 weeks, decreased the rate of isoprenaline-stimulated lactate formation at all insulin concentrations, but significantly decreased the responsiveness of lactate formation only at low insulin concentrations. In the presence of 100 or 10,000 mu-units of insulin/ml, the ability of isoprenaline to suppress the rate of glycogen synthesis was markedly impaired (inhibition at 100 mu-units of insulin/ml and 1 micro-M-isoprenaline: eu- 72.6 +/- 2.9%; hypo-41.0 +/- 2.1%; P less than 0.001). 4. Hyperthyroidism had no effect on the number or affinity of beta-adrenoceptors, defined by 125I-pindolol binding, or beta-adrenoceptor- or forskolin-stimulated adenylate cyclase activity in membrane preparations of gastrocnemius muscle, whereas hypothyroidism increased the beta-adrenoceptor density and decreased the beta-adrenoceptor-stimulated adenylate cyclase activity, without affecting the receptor affinity or forskolin-stimulated adenylate cyclase activity. 5. It is concluded that there is a complex interplay between insulin, catecholamines and thyroid hormones to regulate skeletal-muscle glucose metabolism. The changes observed in muscles in hypothyroidism may be explained, at least in part, by changes in beta-adrenoceptor-G-protein-adenylate cyclase coupling affecting the generation of cyclic AMP and the regulation of some of the key enzymes of glycogen metabolism; in contrast, the changes observed in muscles in hyperthyroidism do not appear to result from alterations at the level of the receptor-mediated second-messenger generation.

The focus of this research is the potential of biomethane in Britain's gas grid. It examines its relative ability to address Britain's sustainability and energy security challenges from an economic perspective. Such research is important because UK is wedded to gas for heat production and power generation and is increasingly dependent on imported gas, in line with shrinking domestic production, and uncertain future trading relationships. Also, dependency on natural gas, threatens Britain achieving its legally-binding carbon budgets. The study included a thorough literature review, primary research to finally uncover the views of key UK market participants plus analytical modelling. The findings reveal that the market is cautiously optimistic, despite reservations regarding feedstock availability and the impending cessation of subsidy approvals. Investors are in greater need of long-term certainty, however, and the challenge of decarbonising heat and heavy-duty transport warrants this. Retail price premiums are polarised but, in line with wholesale costs, relatively high compared to electricity. The key recommendation is for the policymakers to follow precedents in renewable electricity and liquid biofuels, by mandating that energy suppliers, owners of heavy-duty road fleets and occupiers of new buildings purchase biomethane. In tandem, feedstock and grid-entry restrictions must be tackled creatively.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug−drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. KEYWORDS: SERT, NET, dual, reuptake inhibitor, SNRI, SERT RO, α-MMT, pain M anipulation of central nervous system (CNS) levels of the neurotransmitters serotonin (5-HT) and norepinephrine (NE), through inhibition of the corresponding reuptake transporters SERT (serotonin transporter) and NET (norepinephrine transporter), has been a successful strategy for treating several CNS disorders including depression, generalized anxiety disorder, and several chronic pain conditions. 1−6 Several compounds that selectively inhibit these transporters (known as serotonin norepinephrine reuptake inhibitors or SNRIs) are available on the market (compounds 5−8, see Figure 1) and have proven to be safe and effective drugs for the treatment of pain and/or mood disorders. However, these molecules often show more potent inhibition of SERT than NET in vitro (Table 1). Published studies have demonstrated that selective SERT and NET inhibitors can show additive or synergistic analgesic efficacy. 7,8 For our targeted indication of pain, we hypothesized that a SNRI that inhibited SERT and NET with comparable potency would lead to a compound with a superior efficacy and safety profile. Therefore, we undertook to develop a new SNRI that, in a single molecule, improved NET activity versus current SNRIs, retained potent and balanced in vivo activity at both transporters, had good brain exposure, was metabolically stable, and provided minimal drug−drug interaction (DDI) risk to patients on other therapies.Our search for a balanced SNRI led to the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Amine containing compounds have long been a fertile source of reuptake inhibitors with a variety of profiles. 9 SNRIs 5−8 all show a similar pharmacophore, with an amine and an aryl group separated by 2−4 sp 3 hybridized atoms. The pyrrolidines we synthesized and tested represent a conformationally constrained version of this general pharmacophore that maintains potent transporter inhibition. 10 Compound 1 contains several innovative features that make it an improvement over earlier scaffolds. The pyrrolidine ring provided the secondary amine that is common to many reuptake inhibitors, but in a novel constrained geometry. Introduction of the pyridine ring, in place of a phenyl ring, was a key change that delivered both our desired pharmacological profile and...