Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists.

Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as (), (), and (), with improved potency and efficacy. Intriguingly, compounds and showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound , indicating that reducing GPR52 β-arrestin activity with biased agonism results in sustained GPR52 activation.

Orphan GPR52 as an emerging neurotherapeutic target.

GPR52 is a highly conserved, brain-enriched, G-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia.

Bioremediation of contaminated soil and groundwater by biostimulation.

Bioremediation by biostimulation is an attractive alternative to excavation of contaminated soil. Many remediation methods have been tested with some success; however, due to highly variable results in realistic field conditions, they have not been implemented as widely as they might deserve. To ensure success, methods should be validated under site-analogous conditions before full scale use, which requires expertise and local knowledge by the implementers.

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target.

G protein-coupled receptors (GPCRs) are successful druggable targets, making up around 35% of all FDA-approved medications. However, a large number of receptors remain orphaned, with no known endogenous ligand, representing a challenging but untapped area to discover new therapeutic targets. Among orphan GPCRs (oGPCRs) of interest, G protein-coupled receptor 37 (GPR37) is highly expressed in the central nervous system (CNS), particularly in the spinal cord and oligodendrocytes.

Retraction of "Synthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists".

[This retracts the article DOI: 10.1021/acsmedchemlett.9b00050.

Serotonin 5-HT Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro.

A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT receptor (5-HTR) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HTR pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HTR intracellular signaling via changes in subcellular localization in vitro. Using cell lines stably expressing the wild-type Cys23 or the Ser23 variant, we show that 5-HT evokes intracellular calcium release with decreased potency and peak response in the Ser23 versus the Cys23 cell lines.

Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics.

The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-catechol D1R agonists and positive allosteric modulators.

Synthesis and Pharmacological Evaluation of Noncatechol G Protein Biased and Unbiased Dopamine D1 Receptor Agonists.

Noncatechol heterocycles have recently been discovered as potent and selective G protein biased dopamine 1 receptor (D1R) agonists with superior pharmacokinetic properties. To determine the structure-activity relationships centered on G protein or β-arrestin signaling bias, systematic medicinal chemistry was employed around three aromatic pharmacophores of the lead compound (PF2334), generating a series of new molecules that were evaluated at both D1R G-dependent cAMP signaling and β-arrestin recruitment in HEK293 cells. Here, we report the chemical synthesis, pharmacological evaluation, and molecular docking studies leading to the identification of two novel noncatechol D1R agonists that are a subnanomolar potent unbiased ligand (PW0441) and a nanomolar potent complete G protein biased ligand (PW0464), respectively.

Biophysical validation of serotonin 5-HT2A and 5-HT2C receptor interaction.

The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) in the central nervous system are implicated in a range of normal behaviors (e.g., appetite, sleep) and physiological functions (e.

Small-Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models.

Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models.

Impaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor.

Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive.

Walking blindfolded unveils unique contributions of behavioural approach and inhibition to lateral spatial bias.

Healthy individuals display a tendency to allocate attention unequally across space, and this bias has implications for how individuals interact with their environments. However, the origins of this phenomenon remain relatively poorly understood. The present research examined the joint and independent contributions of two fundamental motivational systems - behavioural approach and inhibition systems (BAS and BIS) - to lateral spatial bias in a locomotion task.

Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy.

Background: Currently, no clinical tools use demographic and risk factor information to predict the risk of finding an adenoma in individuals undergoing colon cancer screening. Such a tool would be valuable for identifying those who would most benefit from screening colonoscopy.

Methods: We used baseline data from men and women who underwent screening colonoscopy from the randomized, multicenter National Colonoscopy Study (NCS) to develop and validate an adenoma risk model.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings.

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons.

Angelman syndrome is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced, raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele.

Advancing drug discovery for schizophrenia.

Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, "Advancing Drug Discovery for Schizophrenia" was held March 9-11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia.

Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.

Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D(2) receptor (D(2)R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D(2)R agonists that display signaling bias via β-arrestin-ergic signaling.

Strategies to discover unexpected targets for drugs active at G protein-coupled receptors.

G protein-coupled receptors (GPCRs) are an evolutionarily conserved family of signaling molecules comprising approximately 2% of the human genome; this receptor family remains a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of drug action at GPCRs over the past decade have revealed existing and novel ligands that exhibit polypharmacology-that is, drugs with activity at more than one receptor target for which they were designed. These "off-target" drug actions can be a liability that causes adverse side effects; however, in several cases, drugs with less selectivity demonstrate better clinical efficacy.

A chemical-genetic approach for precise spatio-temporal control of cellular signaling.

Recently we have perfected a chemical-genetic approach to gain precise spatio-temporal control of cellular signaling. This approach entails the cell-type specific expression of mutant G-protein coupled receptors which have been evolved to be activated by the pharmacologically inert drug-like small molecule clozapine N-oxide. We have named these mutant GPCRs DREADDs (Designer Receptors Exclusively Activated by Designer Drugs).

p90 Ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling.

The 5-hydroxytryptamine 2A (5-HT(2A)) receptor is a member of the G protein-coupled receptor superfamily (GPCR) and plays a key role in transducing a variety of cellular signals elicited by serotonin (5-HT; 5-hydroxytryptamine) in both peripheral and central tissues. Recently, we discovered that the ERK/MAPK effector p90 ribosomal S6 kinase 2 (RSK2) phosphorylates the 5-HT(2A) receptor and attenuates 5-HT(2A) receptor signaling. This raised the intriguing possibility of a regulatory paradigm whereby receptor tyrosine kinases (RTKs) attenuate GPCR signaling (i.

Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling.

The 5-HT(2A) serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT(2A) receptor is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT(2A) receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown.

Caveolin-1 and lipid microdomains regulate Gs trafficking and attenuate Gs/adenylyl cyclase signaling.

Lipid rafts and caveolae are specialized membrane microdomains implicated in regulating G protein-coupled receptor signaling cascades. Previous studies have suggested that rafts/caveolae may regulate beta-adrenergic receptor/Galpha(s) signaling, but underlying molecular mechanisms are largely undefined. Using a simplified model system in C6 glioma cells, this study disrupts rafts/caveolae using both pharmacological and genetic approaches to test whether caveolin-1 and lipid microdomains regulate G(s) trafficking and signaling.