Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease.

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HTR) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HTR antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HTR partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, ). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models.

Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression.

A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (, SUVN-911) as a clinical candidate.

A definite measure of occupancy exposures, seeking with non-radiolabeled in vivo 5-HT2A receptor occupancy and in vitro free fractions.

Unbound drug concentration in the brain would be the true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate the clinical dose projection. With the application of mass spectrometry, the current work proposes a definite measure of test drug exposures at serotonin-2A occupancy.

SUVN-502, a novel, potent, pure, and orally active 5-HT6 receptor antagonist: pharmacological, behavioral, and neurochemical characterization.

Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease.

Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT Receptor Partial Agonists.

Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT receptor (5-HTR) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme.

Aripiprazole in an animal model of chronic alcohol consumption and dopamine D₂ receptor occupancy in rats.

Background: Epidemiologic studies and clinical assessment of schizophrenic population have revealed a high incidence of overlap between schizophrenia and addictive disorders.

Objective: The aim of the present investigation was to study the effect of aripiprazole in a preclinical animal model of chronic alcohol self-administration (CASA) and also to evaluate the influence of CASA on plasma pharmacokinetics and dopamine D₂ receptor (D₂R) occupancy in rats.

Methods: The effect of oral administration of aripiprazole (1, 3, and 10 mg/kg) on 4% alcohol intake in CASA was studied for a period of 45 min after a post-dosing interval of 60 min.

Design, synthesis and pharmacological evaluation of 4-(piperazin-1-yl methyl)-N₁-arylsulfonyl indole derivatives as 5-HT₆ receptor ligands.

4-(Piperazin-1-yl methyl)-N(1)-arylsulfonyl indole derivatives were designed and synthesized as 5-HT(6) receptor (5-HT(6)R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity, good PK profile, no CYP liabilities and activity in animal models of cognition.

Design, synthesis, and pharmacological evaluation of piperidin-4-yl amino aryl sulfonamides: novel, potent, selective, orally active, and brain penetrant 5-HT₆ receptor antagonists.

Our initial findings around aryl sulfonamide series led to N-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT(6) receptor (5-HT(6)R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT(6)R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability.

Approach to reduce the non-specific binding in microdialysis.

Measurement of unbound test compound concentrations at the biophase is routinely carried out in the drug discovery. Microdialysis is an established sampling technique for in vivo measurement of endogenous and exogenous compounds and it is commonly used for monitoring true concentrations. Endogenous compounds like neurotransmitters and neuropeptides in the brain are routinely evaluated as a proof of pharmacological activity of test compounds.

Pharmacokinetic profiling of efavirenz-emtricitabine-tenofovir fixed dose combination in pregnant and non-pregnant rats.

During pregnancy, the disposition of various drugs is altered due to changes in physiological condition, maternal gastrointestinal absorption, gastric secretion and motility. A fixed dose combination of antiretrovirals is commonly prescribed for the treatment of HIV infection. There is a need to understand the pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir in fixed dose combination during pregnancy.

Methyllycaconitine: a non-radiolabeled ligand for mapping α7 neuronal nicotinic acetylcholine receptors - in vivo target localization and biodistribution in rat brain.

Introduction: Reduction of cerebral cortical and hippocampal α7 neuronal nicotinic acetylcholine receptor (nAChR) density was observed in the Alzheimer's disease (AD) and other neurodegenerative diseases. Mapping the subtypes of nAChRs with selective ligand by viable, quick and consistent method in preclinical drug discovery may lead to rapid development of more effective therapeutic agents. The objective of this study was to evaluate the use of methyllycaconitine (MLA) in non-radiolabeled form for mapping α7 nAChRs in rat brain.

Rat thalamic α₄β₂ neuronal nicotinic acetylcholine receptor occupancy assay using LC-MS/MS.

Introduction: In vivo brain receptor occupancy has been the key assay in driving preclinical drug discovery program and there is a need to hasten this screening step. Radiolabeled methods, which are time consuming and expensive, are most widely employed to measure receptor occupancy. Thus we sought to develop and validate an alternative novel approach for measuring rat brain α₄β₂ neuronal nicotinic acetylcholine receptor occupancy using high performance liquid chromatography combined with tandem mass spectrometric detector (LC-MS/MS).

In vivo receptor occupancy assay of histamine H₃ receptor antagonist in rats using non-radiolabeled tracer.

Introduction: Rapid and reliable preclinical receptor occupancy measurement at the target organ in relevant species is critical in accelerating the drug hunting process. The aim of this study was to develop in vivo receptor occupancy assay for histamine H₃ receptors (H₃R) using the non-radiolabeled GSK189254 as a tracer and to correlate the occupancy-exposure relationship for H₃R antagonists in the rats.

Methods: In vivo tracer characterization studies like brain regional distribution, dose and time dependent uptake were carried out for GSK189254 in the male Wistar rats after intravenous administration.

Exploring dried blood spot sampling technique for simultaneous quantification of antiretrovirals: lamivudine, stavudine and nevirapine in a rodent pharmacokinetic study.

A high-performance liquid chromatography/positive ion electrospray tandem mass spectrometry method for the simultaneous quantification of lamivudine, stavudine and nevirapine was developed and validated in dried blood spot (DBS) cards. The analytes were separated using an isocratic mobile phase on a reverse phase column and analyzed by MS/MS in the MRM mode using the respective [M + H]⁺ ions, m/z 230-112 for lamivudine, m/z 225-127 for stavudine, m/z 267-226 for nevirapine, m/z 383-337 for zidovudine (IS). The lower limit of quantification was 1 ng/mL for both lamivudine and stavudine and 10 ng/mL for nevirapine.

Concurrent administration of atypical antipsychotics and donepezil: drug interaction study in rats.

Psychotic and behavioral symptoms are common in patients with dementia. Thus, it is rational to assume that patients with dementia would gain benefit from combination therapy of an antipsychotic agent and a cognitive enhancer. Antipsychotics are not approved by the US FDA in elderly patients with dementia but their use is still prevalent in other population.

Quantification of methyllycaconitine, selective α7 nicotinic receptor antagonist, in rodent plasma and brain tissue by liquid chromatography tandem mass spectrometry--application to neuropharmacokinetics of methyllycaconitine in rats.

A sensitive high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of methyllycaconitine (MLA) in rat plasma and brain tissue. Following acetonitrile protein precipitation, the analyte was separated using a gradient mobile phase on a reversed-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M + H](+) ions, m/z 683-216 for MLA and m/z 260-116 for the internal standard. The assay exhibited a linear dynamic range of 0.

A simple and rapid method to collect the cerebrospinal fluid of rats and its application for the assessment of drug penetration into the central nervous system.

Many central nervous system (CNS) drug discovery programs require the successful collection of cerebrospinal fluid (CSF) for assessing CNS penetration and distribution of new chemical entities. The objective of the present investigation was to simplify the technique for collecting maximum CSF from cisterna magna of the rats. Rat was anesthetized with 5% halothane and positioned in a stereotaxic frame.