A5049644101- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Estrogen and related hormone effects
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Neuropeptides and Animal Physiology
- Cancer-related Molecular Pathways
- Molecular Sensors and Ion Detection
- Phenothiazines and Benzothiazines Synthesis and Activities
- Chemical Synthesis and Analysis
- Neuroendocrine regulation and behavior
- Coordination Chemistry and Organometallics
- Advanced Breast Cancer Therapies
- Bioactive Compounds and Antitumor Agents
- Synthesis of heterocyclic compounds
- Radical Photochemical Reactions
- Sperm and Testicular Function
- Reproductive Biology and Fertility
- Insect and Pesticide Research
- Mitochondrial Function and Pathology
- Amino Acid Enzymes and Metabolism
- Pain Mechanisms and Treatments
- Pulmonary Hypertension Research and Treatments
- Organic Chemistry Cycloaddition Reactions
Innovative Design Labs (United States)
2017-2025
University of Minnesota
2016-2025
Twin Cities Orthopedics
2022
Omneuron (United States)
2011
Sunesis (United States)
2007-2010
University of Oregon
1995-2000
In-Q-Tel
1997
University of Southern California
1997
University of California, Irvine
1997
CACI International (United States)
1997
Abstract Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity inhibitors exist. Cyclin-dependent 2 (CDK2) is a many therapeutic indications, including non-hormonal contraception. However, inhibitor against this with exquisite has not reached market...
Although cyclin-dependent kinase 2 (CDK2) is a validated target for both cancer and contraception, developing CDK2 inhibitor with exquisite selectivity has been challenging due to the structural similarity of ATP-binding site, where most inhibitors bind. We previously discovered an allosteric pocket in potential bind selective compound then structurally confirmed anthranilic acid scaffold that binds this high affinity. These are over similar CDK1 show contraceptive potential. Herein, we...
Abstract The cation channel of sperm (CatSper) is a validated target for nonhormonal male contraception, but it lacks selective blockers, hindering studies to establish its role in both motility and capacitation. Via an innovative calcium uptake assay utilizing human we discovered novel inhibitors CatSper function from high‐throughput screening campaign 72,000 compounds. Preliminary SAR was established seven hit series. HTS hits or their more potent analogs blocked potassium‐induced...
BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), primary receptor nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, immunohistochemistry characterize signaling biological effects on...
A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent selective antagonist the NR1A/2B subtype NMDA receptors. Substitution on benzyl group 8 did not significantly affect potency, while addition hydrogen bond donors para position phenyl enhanced potency. Addition hydroxyl moiety 4-position piperidine slightly reduced...
Neuroactive steroids, including endogenously occurring metabolites of progesterone and deoxycorticosterone as well their synthetic derivatives, are positive allosteric modulators the gamma-aminobutyric acid (GABA)A receptor complex. They inhibit binding [35S]t-butylbicyclophosphorothionate ([35S]TBPS), enhance [3H]flunitrazepam, potentiate GABA-evoked chloride currents agonist-stimulated 36Cl- uptake. The structure-activity relationship for 31 neuroactive steroids related compounds was...
Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of male mice results complete infertility, making it an attractive target for contraception. characterized by high affinity the cardiac glycoside ouabain. With goal discovering selective inhibitors function, ouabain derivatives were modified at glycone (C3) lactone (C17) domains. Ouabagenin analogue 25, carrying benzyltriazole moiety C17, picomolar inhibitor α4, with outstanding...
Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as therapy Alzheimer's disease (AD). However, is known to process multiple substrates addition amyloid precursor protein (APP), most notably Notch, which has limited clinical development inhibitors targeting this enzyme. It been postulated that APP substrate selective would be preferable non-selective from safety perspective AD therapy.In vitro assays monitoring inhibitor potencies at γ-site...
Abstract Retinoic acid receptor alpha (RARα) antagonist ER‐50891 and 15 analogs were prepared tested in vitro for potency selectivity at RARα, RARβ, RARγ using transactivation assays. Minor modifications to the parent molecule such as introduction of a C4 tolyl group place phenyl on quinoline moiety slightly increased RARα but larger substituents significantly decreased potency. Replacement pyrrole with triazole, amides, or double bond produced inactive compounds. was found be stable male...
Two naturally occurring metabolites of progesterone, 3α-hydroxy-5α- and 5β-pregnan-20-one (1 2), are potent allosteric modulators the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series 3β-substituted derivatives 1 2 was prepared. Small lipophilic groups generally maintain potency in both 5α- 5β-series determined inhibition [35S]TBPS binding. In 5α-series, 3β-ethyl, -propyl,...
An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor body temperature concurrently measured 30 before treatment. Identical procedures used test triazolam zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) steroids (10-30 produced dose-dependent increases in non-rapid eye movement...
Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion ataxin-1 protein (ATXN1), phosphorylation ATXN1 at the serine 776 residue (ATXN1-pS776) plays significant role toxicity. Utilizing biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine Protein Kinase A (PKA) as an effector...
Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A 5-HT2B. A rat model monocrotaline (MCT)-induced PAH was used to examine potential beneficial effects RP5063, 5-HT receptor modulator. After single 60mg/kg dose MCT, rats were gavaged twice-daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10mg/kg), sildenafil (50mg/kg) for 28 days. at as low 1mg/kg, b.i.d. reduced...
Abstract Testis‐specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high‐throughput screen of ≈17 000 compounds using a mobility shift assay identified two potent series inhibitors having pyrrolopyrimidine or pyrimidine core. The 10 (IC 50 22 n m ; GSK2163632A) and the 17 31 ALK inhibitor 1) are most TSSK2 in these series, which contain first sub‐100 nanomolar any TSSK isoform reported, except broad staurosporine. novel, compound 19 66...
TGR5 agonists are potential therapeutics for a variety of conditions including type 2 diabetes, obesity, and inflammatory bowel disease. After screening library chenodeoxycholic acid (CDCA) derivatives, it was determined that range modifications could be made to the moiety CDCA which significantly increased agonist potency. Surprisingly, methylation 7-hydroxyl led further dramatic increase in potency, allowing identification 5.6 nM 17.
Synapse loss and dendritic damage correlate with cognitive decline in many neurodegenerative diseases, underlie neurodevelopmental disorders, are associated environmental drug-induced CNS toxicities. However, screening assays designed to measure of synaptic connections between live cells lacking. Here, we describe the design validation ASIA (automated imaging assay), an efficient approach label, image, analyze synapses neurons. Using viral transduction express fluorescent proteins that label...
A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism NMDA receptor glycine site. Glycine site affinity determined using a [3H]DCKA binding assay in rat brain membranes electrophysiologically Xenopus oocytes expressing 1a/2C subunits cloned receptors. Selected compounds were also assayed AMPA receptors poly(A)+ RNA. QTOs prepared by nitrosation 2,4-quinolinediols. Structure−activity studies indicated that substitutions the 5-, 6-,...
Neuroactive steroids that allosterically modulate GABAA receptors have potential uses as anticonvulsants, anxiolytics, and sedative−hypnotic agents. Recently, a series of pregnanes substituted with simple alkyl groups at the 3β-position were synthesized found to be active in vitro. The present report describes synthesis 3α-hydroxy-3β-(phenylethynyl)pregnan-20-ones their vitro structure−activity relationship determined by potency for inhibition [35S]TBPS binding rat brain membranes....
Although glycine has been assumed to be the sole endogenous coagonist at NMDA-associated receptors, recent descriptions of D-serine in brain indicate that this assumption is probably not valid. D-Serine a stereospecific agonist receptor, with an affinity equal or greater than but no for strychnine-sensitive receptor. In current studies, we assessed levels and metabolic sources rat neocortical synaptosomal preparations. Previous studies have demonstrated CNS serine are synthesized de novo...