Development of : A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder.

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, () was identified as a novel M orthosteric antagonist with high potency (human M IC = 36 nM), M subtype selectivity (>100-fold selectivity against human M) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry.

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M PAMs.

This letter describes progress towards an M PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.

Replication of Associations with Electrocardio-graphic Traits in African Americans from Clinical and Epidemiologic Studies.

The NAv1.5 sodium channel α subunit is the predominant α-subunit expressed in the heart and is associated with cardiac arrhythmias. We tested five previously identified variants (rs7374138, rs7637849, rs7637849, rs7629265, and rs11129796) for an association with PR interval and QRS duration in two unique study populations: the Third National Health and Nutrition Examination Survey (NHANES III, n= 552) accessed by the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) and a combined dataset (n= 455) from two biobanks linked to electronic medical records from Vanderbilt University (BioVU) and Northwestern University (NUgene) as part of the electronic Medical Records & Genomics (eMERGE) network.

Detection of pleiotropy through a Phenome-wide association study (PheWAS) of epidemiologic data as part of the Environmental Architecture for Genes Linked to Environment (EAGLE) study.

We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999-2000, and 2001-2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950).

Rare variant APOC3 R19X is associated with cardio-protective profiles in a diverse population-based survey as part of the Epidemiologic Architecture for Genes Linked to Environment Study.

Background: A founder mutation was recently discovered and described as conferring favorable lipid profiles and reduced subclinical atherosclerotic disease in a Pennsylvania Amish population. Preliminary data have suggested that this null mutation APOC3 R19X (rs76353203) is rare in the general population.

Methods And Results: To better describe the frequency and lipid profile in the general population, we as part of the Population Architecture using Genomics and Epidemiology I Study and the Epidemiological Architecture for Genes Linked to Environment Study genotyped rs76353203 in 1113 Amish participants from Ohio and Indiana and 19 613 participants from the National Health and Nutrition Examination Surveys (NHANES III, 1999 to 2002, and 2007 to 2008).