Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less β-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.

https://jpet.aspetjournals.org/content/jpet/early/2013/01/08/jpet.112.201616.full.pdf

A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.12445

The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(10)00182-6.pdf

Therapeutic potential of β-arrestin- and G protein-biased agonists

Binding modes and molecular mechanisms of several allosteric modulators of a prototypical G-protein-coupled receptor are revealed using atomic-level simulations and validated by the rational design of a modulator with substantially altered effects. A third of clinically used drugs elicit their biological effects via a G-protein-coupled receptor (GPCR), usually by binding at the orthosteric (primary ligand-binding) site, in competition with the ligands that naturally regulate receptor signalling. The design of small molecules able to selectively modulate a GPCR by binding to an allosteric site is a desirable goal, but difficult to achieve because neither the binding modes nor the molecular mechanisms of such molecules are known. In this manuscript, the authors used molecular dynamics simulations, with experimental validation, to determine where and how structurally diverse allosteric modulators bind to the M2 muscarinic acetylcholine receptor, which is essential for the physiological control of cardiovascular function. Despite substantial structural diversity of the small molecule ligands, the molecules all formed cation-π interactions with clusters of aromatic residues in the receptor's extracellular vestibule, about 15 A from the ligand-binding pocket. These findings may facilitate the rational design of allosteric modulators targeting muscarinic and related GPCRs. The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known1,2. Here we determine binding sites, bound conformations and specific drug–receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation–π interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 A from the classical, ‘orthosteric’ ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator’s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.

Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs

The forebrain cholinergic system promotes higher brain function in part by signaling through the M1 muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M1 receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M1 mAChR. BQCA reduces the concentration of ACh required to activate M1 up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 μM. Furthermore studies in M1−/− mice demonstrates that BQCA requires M1 to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M1 allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces β-arrestin recruitment to M1, suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M1 receptor and represents a promising therapeutic strategy for cognitive disorders.

https://www.pnas.org/content/pnas/106/37/15950.full.pdf

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation

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Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation