The utilization of CO2 to generate chemical fuels, such as formic acid, is a potentially beneficial route to balance carbon emissions and reduce dependence on fossil fuels. The development of efficient catalysts for CO2 hydrogenation is needed to implement this fuel generation. In the molecular catalyst design presented here, we covalently attached a rhodium complex, ([RhI(PNglyP)2]−, where PNglyP is defined as PEt2 –CH2–N(CH2CO2 –)–CH2–PEt2 ) to a protein scaffold, (lactococcal multidrug resistant regulator from Lactococcus lactis) to use the protein environment around the metal center to control substrate delivery and therefore enable and improve catalytic activity. The reactivities of the rhodium complex and the synthetic metalloenzyme were characterized by high-pressure operando NMR techniques. In solution, the rhodium complex alone is not a catalyst for CO2 hydrogenation. Incorporation of the rhodium complex into the protein scaffold resulted in a gain of function, turning on CO2 hydrogenation activity. The metalloenzyme displayed a turnover frequency of 0.38 ± 0.03 h–1 at 58 atm and 298 K and achieved an average turnover number of 14 ± 3. Proposed catalytic intermediates generated and characterized suggest that the protein scaffold enables catalysis by facilitating the interaction between CO2 and the hydride donor intermediate.

Background and Purpose: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. Experimental Approach: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M 2 receptors was modelled in silico. Key Results: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,-6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2Hpyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M 2 muscarinic receptors and displaying bias towards the G i signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. Conclusions and Implications: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M 2 and M 4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.

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Aldehydes with bulky substituents in the ortho-positions have been historically difficult in porphyrin synthesis, presumably owing to steric hindrance around the reactive site. We have used mechanochemistry for the simple, room-temperature synthesis of tetra-meso-substituted porphyrins. In the present study, mesitaldehyde undergoes acid-catalyzed mechanochemical condensation with pyrrole to give meso-tetrakis[2,4,6-(trimethyl)phenyl]porphyrin (TMP) after oxidation in solution. Yields are similar to those obtained using high-temperature porphyrin synthesis, although they remain significantly lower than some optimized room-temperature, solution-based methods. Yields of the mechanochemical synthesis were found to increase slightly upon longer exposure to an organic oxidizing agent in solution. This indicates that the mechanochemical condensation step may be more successful than initially realized. This work shows that mechanochemistry is a successful, simple, room-temperature method for producing tetra-meso-substituted porphyrins with bulky substituents.