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.

Discovery of VU0467319: an M Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

Herein we detail the of VU0467319 (VU319), an M Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 () is a moderately potent M PAM (M PAM EC = 492 nM ± 2.9 nM, 71.

Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3-]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3-]pyrimidine tricycle core provided lead compound, , with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

Development of VU6036864: A Triazolopyridine-Based High-Quality Antagonist Tool Compound of the M Muscarinic Acetylcholine Receptor.

While the muscarinic acetylcholine receptor mAChR subtype 5 (M) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, () showed exquisite potency (human M IC = 20 nM), good subtype selectivity (>500 fold selectivity against human M), desirable brain exposure ( = 0.

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.

M-selective muscarinic allosteric modulation enhances cognitive flexibility and effective salience in nonhuman primates.

Acetylcholine (ACh) in cortical neural circuits mediates how selective attention is sustained in the presence of distractors and how flexible cognition adjusts to changing task demands. The cognitive domains of attention and cognitive flexibility might be differentially supported by the M muscarinic acetylcholine receptor (mAChR) subtype. Understanding how M mAChR mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimer's disease or schizophrenia.

The Evolving Role of Animal Models in the Discovery and Development of Novel Treatments for Psychiatric Disorders.

Historically, animal models have been routinely used in the characterization of novel chemical entities (NCEs) for various psychiatric disorders. Animal models have been essential in the in vivo validation of novel drug targets, establishment of lead compound pharmacokinetic to pharmacodynamic relationships, optimization of lead compounds through preclinical candidate selection, and development of translational measures of target occupancy and functional target engagement. Yet, with decades of multiple NCE failures in Phase II and III efficacy trials for different psychiatric disorders, the utility and value of animal models in the drug discovery process have come under intense scrutiny along with the widespread withdrawal of the pharmaceutical industry from psychiatric drug discovery.

Selective M muscarinic acetylcholine receptor negative allosteric modulator VU6008667 blocks acquisition of opioid self-administration.

Recent evidence suggests that inhibition of the M muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use disorder (OUD). Previous studies from our group and others have demonstrated that acute administration of the long-acting M negative allosteric modulator (NAM) ML375 attenuates established self-administration of cocaine, ethanol, oxycodone, and remifentanil in rats. In the present study, we characterized the effects of acute and repeated administration of the novel, short-acting M NAM VU6008667 on the reinforcing effects of oxycodone and reinstatement of oxycodone-seeking behaviors in male Sprague-Dawley rats, as well as on physiological withdrawal from oxycodone.

Discovery of a potent M antagonist with improved clearance profile. Part 2: Pyrrolidine amide-based antagonists.

This Letter describes our ongoing effort to improve the clearance of selective M antagonists. Herein, we report the replacement of the previously disclosed piperidine amide (4, disclosed in Part 1) with a pyrrolidine amide core. Several compounds within this series provided good potency, subtype selectivity, and low to moderate clearance profiles.

Discovery of a potent M antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists.

The lack of potent and selective tool compounds with pharmaceutically favorable properties limits the in vivo understanding of muscarinic acetylcholine receptor subtype 5 (M) biology. Previously, we presented a highly potent and selective M antagonist VU6019650 with a suboptimal clearance profile as our second-generation tool compound. Herein, we disclose our ongoing efforts to generate next-generation M antagonists with improved clearance profiles.

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.

Partial mGlu Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without Affecting Cognition or Quantitative EEG.

Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu) demonstrate anxiolytic-like and antidepressant-like effects yet concern regarding adverse effect liability remains. Functional coupling of mGlu with ionotropic -methyl-D-aspartate receptors (NMDARs) represents a potential mechanism through which full inhibition leads to adverse effects, as NMDAR inhibition can induce cognitive impairments and psychotomimetic-like effects. Recent development of "partial" mGlu NAMs, characterized by submaximal but saturable levels of blockade, may represent a novel development approach to broaden the therapeutic index of mGlu NAMs.

Sexual Dimorphism in Stress-induced Hyperthermia in SNAP25Δ3 mice, a mouse model with disabled Gβγ regulation of the exocytotic fusion apparatus.

Behavioral assays in the mouse can show marked differences between male and female animals of a given genotype. These differences identified in such preclinical studies may have important clinical implications. We recently made a mouse model with impaired presynaptic inhibition through Gβγ-SNARE signaling.

Acetylcholine Muscarinic M Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents.

Background: Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function.

Methods: We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate-putamen of human AUD samples to identify potential therapeutic targets.

to Translation of Allosteric Modulator Concentration-Effect Relationships: Implications for Drug Discovery.

Allosteric modulation of GPCRs represents an increasingly explored approach in drug development. Due to complex pharmacology, however, the relationship(s) between modulator properties determined with concentration-effect phenomena is frequently unclear. We investigated key pharmacological properties of a set of metabotropic glutamate receptor 5 (mGlu) positive allosteric modulators (PAMs) and their relevance to concentration-response relationships.

Phenotypic profiling of mGlu knockout mice reveals new implications for neurodevelopmental disorders.

Neurodevelopmental disorders are characterized by deficits in communication, cognition, attention, social behavior and/or motor control. Previous studies have pointed to the involvement of genes that regulate synaptic structure and function in the pathogenesis of these disorders. One such gene, GRM7, encodes the metabotropic glutamate receptor 7 (mGlu ), a G protein-coupled receptor that regulates presynaptic neurotransmitter release.

Selective allosteric modulation of muscarinic acetylcholine receptors for the treatment of schizophrenia and substance use disorders.

Muscarinic acetylcholine receptor (mAChRs) subtypes represent exciting new targets for the treatment of schizophrenia and substance use disorder (SUD). Recent advances in the development of subtype-selective allosteric modulators have revealed promising effects in preclinical models targeting the different symptoms observed in schizophrenia and SUD. M PAMs display potential for addressing the negative and cognitive symptoms of schizophrenia, while M PAMs exhibit promise in treating preclinical models predictive of antipsychotic-like activity.

The Role of Estrogen in Brain and Cognitive Aging.

There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models.

Acute Negative Allosteric Modulation of M Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception.

Opioid use disorder (OUD) is a debilitating neuropsychiatric condition characterized by compulsive opioid use, dependence, and repeated relapse after periods of abstinence. Given the high risk of developing OUD following prescription opioid use, the continued need for opioid-induced analgesia, and the limitations of current OUD treatments, it is necessary to develop novel, non-opioid-based treatments for OUD and decrease abuse potential of prescription opioids. Recent evidence suggests that negative allosteric modulation (NAM) of the M muscarinic acetylcholine receptor (M mAChR) may provide an alternative therapeutic approach for the treatment of OUD.

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.

VU6005806/AZN-00016130, an advanced M positive allosteric modulator (PAM) profiled as a potential preclinical development candidate.

This letter describes progress towards an M PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate.

Discovery of VU2957 (Valiglurax): An mGlu Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease.

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive and pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies.