A multiomic network approach uncovers disease modifying mechanisms of inborn errors of metabolism.

For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited in part explaining their unmet medical needs. We hypothesize that the expressivity of IEM disease phenotypes is affected by the activity of specific modifier pathways, which is controlled by rare and common polygenic variation. To identify these modulating pathways, we used RNA sequencing to generate molecular signatures of IEM in disease relevant tissues.

Cryo-EM reveals a new allosteric binding site at the M mAChR.

The M muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site has posed significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M mAChR and its allosteric binding sites has remained limited.

Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu.

Synthesis of the Dimeric Diarylheptanoids Alpinidinoid C and Officinine B Enabled by Blue-Light-Mediated Triple-Minisci-Type Alkylation.

The first syntheses of the natural products alpinidinoid C and officinine B are reported. These unusual dimeric diarylheptanoids were accessed from a 3-substituted pyridine intermediate via a blue-light-mediated, triple-Minisci-type alkylation. Very few reports utilize -(acyloxy)phthalimides (NAPs) in the construction of natural products, and the syntheses reported herein highlight the power of this methodology toward the orthogonal construction of highly substituted arenes.

Discovery of VU6007496: Challenges in the Development of an M Positive Allosteric Modulator Backup Candidate.

Herein we report progress toward a backup clinical candidate to the M positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3-]pyridine-based M PAM VU6007477 to isomeric pyrrolo[3,2-]pyridine and thieno[3,2-]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2-]pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability screen, preventing further development.

Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.

Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT) agonists. Specifically, we examine the 5-HT pharmacology of the direct indazole analogs of 5-methoxy-,-dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT subtype selectivity for these analogs, particularly for the 5-HT receptor subtype. Within this series, the potent analog VU6067416 () was optimized to have suitable preclinical pharmacokinetic properties for dosing, although potent 5-HT agonist activity precluded further characterization for this series.

Development of a Peripherally Restricted 5-HT Partial Agonist for Treatment of Pulmonary Arterial Hypertension.

Ligands for the serotonin 2B receptor (5-HT) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia.

Development of a Selective and High Affinity Radioligand, [H]VU6013720, for the M Muscarinic Receptor.

M muscarinic receptors are highly expressed in the striatum and cortex, brain regions that are involved in diseases such as Parkinson's disease, schizophrenia, and dystonia. Despite potential therapeutic advantages of specifically targeting the M receptor, it has been historically challenging to develop highly selective ligands, resulting in undesired off-target activity at other members of the muscarinic receptor family. Recently, we have reported first-in-class, potent, and selective M receptor antagonists.

2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery.

The cardiotoxicity associated with -ethyl-dexfenfluramine (norDF) and related agonists of the serotonin receptor 2B (5-HT) has solidified the receptor's place as an "antitarget" in drug discovery. Conversely, a growing body of evidence has highlighted the utility of 5-HT antagonists for the treatment of pulmonary arterial hypertension (PAH), valvular heart disease (VHD), and related cardiopathies. In this Perspective, we summarize the link between the clinical failure of fenfluramine-phentermine (fen-phen) and the subsequent research on the role of 5-HT in disease progression, as well as the development of drug-like and receptor subtype-selective 5-HT antagonists.

Alkylation of H-sulfoximines under Mitsunobu-type conditions.

Previously described approaches for the alkylation of H-sulfoximines typically rely either on transition metal catalysis, or the use of traditional alkylation reagents and strong bases. Herein, we report a straightforward alkylation of diverse H-sulfoximines under simple Mitsunobu-type conditions, despite the unusually high p of the H center.

Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen.

Antagonists of the serotonin receptor 2B (5-HT) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier.

DARK Classics in Chemical Neuroscience: Methaqualone.

Commonly known as "Quaaludes," methaqualone () is a sedative-hypnotic medication, with effects resembling barbiturates and other downers, that exerts its effects through modulation of γ-aminobutyric acid type A receptors (GABAR). Following the discovery of the sedative and euphoric effects of methaqualone (), it was quickly adopted by pharmaceutical companies and promoted by clinicians around the world as a "safe" sleeping pill option, and for a period it was available over the counter. The popularity of methaqualone () soared worldwide, and many people began to use it recreationally for its sedative-hypnotic-like psychoactive effects.

Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M muscarinic acetylcholine receptor.

In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19).

Peroxisomal L-bifunctional protein (EHHADH) deficiency causes male-specific kidney hypertrophy and proximal tubular injury in mice.

Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO.

Discovery of the First Selective M Muscarinic Acetylcholine Receptor Antagonists with Antiparkinsonian and Antidystonic Efficacy.

Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics.

Discovery of VU6028418: A Highly Selective and Orally Bioavailable M Muscarinic Acetylcholine Receptor Antagonist.

Herein, we report the SAR leading to the discovery of VU6028418, a potent M mAChR antagonist with high subtype-selectivity and attractive DMPK properties and across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.

Discovery of a novel class of heteroaryl-pyrrolidinones as positive allosteric modulators of the muscarinic acetylcholine receptor M.

This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M (mAChR M). Through the continued optimization of M PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M mAChR, and no M agonism.

Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains.

The glutaric acidurias are a group of inborn errors of metabolism with different etiologies. Glutaric aciduria type 3 (GA3) is a biochemical phenotype with uncertain clinical relevance caused by a deficiency of succinyl-CoA:glutarate-CoA transferase (SUGCT). SUGCT catalyzes the succinyl-CoA-dependent conversion of glutaric acid into glutaryl-CoA preventing urinary loss of the organic acid.

DARK Classics in Chemical Neuroscience: Carfentanil.

Because of its remarkable potency and relative ease of synthesis, carfentanil () has recently emerged as a problematic contaminant in other drugs of abuse. Carfentanil and its close analogues, currently approved only for large animal veterinary medicine, have found use both as illicit additives to the clandestine manufacture of scheduled drugs and as chemical weapons. In this Review, the background, synthesis, manufacture, metabolism, pharmacology, approved indications, dosage, and adverse effects of carfentanil will be discussed along with its emergence as a key player in the ongoing opioid crisis.

Synthesis of Substituted 6,7-Dihydro-5-pyrrolo[2,3-]pyridazines/pyrazines via Catalyst-Free Tandem Hydroamination-Aromatic Substitution.

Herein, we report an efficient and operationally simple synthesis of 6,7-dihydro-5-pyrrolo[2,3-]pyridazines and 6,7-dihydro-5-pyrrolo[2,3-]pyrazines via a tandem hydroamination-SAr sequence that makes use of mild reagents under catalyst-free conditions in moderate to high yields. This chemistry expands the known scope of pyridazine/pyrazine chemistry and can be applied toward the synthesis of novel drug-like molecules with favorable bioactivity and pharmacokinetic properties.

The C. elegans CHP1 homolog, pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen.

Caenorhabditis elegans are soil-dwelling nematodes and models for understanding innate immunity and infection. Previously, we developed a novel fluorescent dye (KR35) that accumulates in the intestine of C. elegans and reports a dynamic wave in intestinal pH associated with the defecation motor program.

Dual Pharmacophores Explored via Structure-Activity Relationship (SAR) Matrix: Insights into Potent, Bifunctional Opioid Ligand Design.

Short-acting μ-opioid receptor (MOR) agonists have long been used for the treatment of severe, breakthrough pain. However, selective MOR agonists including fentanyl and morphine derivatives are limited clinically due to high risks of dependence, tolerance, and respiratory depression. We recently reported the development of a long-acting, bifunctional MOR agonist/δ-opioid receptor (DOR) antagonist analgesic devoid of tolerance or dependence in mice (AAH8, henceforth referred to as 2B).