Cipepofol (HSK3486), a sedative-hypnotic agent, is a gamma-aminobutyric acid (GABA) receptor potentiator[1].
4α-Phorbol 12,13-didecanoate (4αPDD) is a TRPV4 agonist with antidipsogenic effects. 4α-Phorbol 12,13-didecanoate promotes Ca2+ influx[1].
Glycine-13C2,15N,d2 is the deuterium, 13C and 15N labeled Glycine[1]. Glycine is an inhibitory neurotransmitter in the CNS and also acts as a co-agonist along with glutamate, facilitating an excitatory potential at the glutaminergic N-methyl-D-aspartic acid (NMDA) receptors[2].
SKF 81297 is a potent and selective dopamine D1 receptor agonist[1].
3-Fucosyllactose (3-Fucosyl-D-lactose) is one of the major fucosylated oligosaccharides found in human breast milk. 3-Fucosyllactose shows prebiotic, immunomodulator, neonatal brain development, and antimicrobial function[1].
Clovamide (trans-Clovamide), a natural phenolic compound, is a potent antioxidant. Clovamide is an excellent ROS and oxygen radical scavenger. Clovamide also has anti-inflammatory and neuroprotective effects[1][2]. Clovamide is an anti-microbial with activity against the human pathogens influenza A subtype H5N1, Trypanosoma evansi, and Heliobacter pylori[3].
Osmanthuside B can be isolated from Pseuderanthemum carruthersii (Seem.) Guill. var. atropurpureum (Bull.) Fosb and has weak acetylcholinesterase inhibitory activity[1].
R-(-)-Oxaprotiline (Levoprotiline) hydrochloride is the R-enantiomer of Oxaprotiline. Oxaprotiline is a tetracyclic antidepressant agent[1].
Nordoxepin D3 hydrochloride (Desmethyldoxepin D3 hydrochloride) is the deuterium labeled Nordoxepin hydrochloride. Nordoxepin hydrochloride is an active metabolite of Doxepin hydrochloride (HY-B0725), which is an orally active tricyclic antidepressant[1].
Duloxetine hydrochloride is a serotonin-norepinephrine reuptake inhibitor (SNRI) with Ki of 4.6 nM, used for treatment of major depressive disorder and generalized anxiety disorder (GAD).Target: SNRIDuloxetine (sold under the brand names Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela, Dulane) is a serotonin-norepinephrine reuptake inhibitor(SNRI) manufactured and marketed by Eli Lilly. It is prescribed for major depressive disorder and generalized anxiety disorder (GAD). Duloxetine also has approval for use in osteoarthiritis and musculoskeletal pain. Duloxetine failed the US approval for stress urinary incontinence amidst concerns over liver toxicity and suicidal events; however, it was approved for this indication in Europe, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery. It can also relieve the symptoms of painful peripheral neuropathy, particularly diabetic neuropathy, and it is used to control the symptoms of fibromyalgia.The main uses of duloxetine are in major depressive disorder, general anxiety disorder, stress urinary incontinence, painful peripheral neuropathy,fibromyalgia, and chronic musculoskeletal pain associated with osteoarthritis and chronic lower back pain. It is being studied for various other indications.
FM1-43, a styryl dye used to study endocytosis and exocytosis, behaves as a permeant blocker of the hair-cell mechanotransducer channel. FM1-43 also reduces the ototoxic effects of the aminoglycoside antibiotic neomycin sulfate[1].
AMG 579 is a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A) with an IC50 of 0.1 nM.
Neuronostatin-13 human is a 13-amino acid peptide hormone encoded by the somatostatin gene and plays an important role in the regulation of hormonal and cardiac function.
Sp-8-CPT-cAMPS, a cAMP analog, is a potent and selective activator of the cAMP-dependent protein kinas A (PKA I and PKA II). Sp-8-CPT-cAMPS selects site A of RI compares to site A of RII by 153-fold and site B of RII compares to site B of RI by 59-fold[1][2].
L-Cysteinesulfinic acid is a potent agonist at several rat metabotropic glutamate receptors (mGluRs) with pEC50s of 3.92±0.03, 4.6±0.2, 3.9±0.2, 2.7±0.2, 4.0±0.2, and 3.94±0.08 for mGluR1, mGluR5, mGluR2, mGluR4, mGluR6, and mGluR8, respectively.
3'-Methoxyflavonol is a selective agonist of neuromedin U 2 receptor (NMU2R).
Hexanoylglycine is an endogenous metabolite present in Urine that can be used for the research of Ethylmalonic Encephalopathy[1][2].
Flibanserin is a novel multifunctional serotonin agonist and antagonist (MSAA) that improves sexual functioning in premenopausal women who suffer from reduced sexual interest and desire.IC50 value:Target: serotoninin vivo: The multifunctional serotonergic agent Flibanserin is both a serotonin 1A agonist and a serotonin 2A antagonist. Flibanserin theoretically improves sexual functioning by enhancing downstream release of dopamine and norepinephrine while reducing serotonin release in the brain circuits that mediate symptoms of reduced sexual interest and desire. Flibanserin, a new molecular entity for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. Flibanserin improves interest in and desire for sex by hypothetically targeting these circuits and causing the release of dopamine and norepinephrine while also reducing the release of serotonin. Flibanserin has demonstrated clinical efficacy in premenopausal women who have reduced interest in and desire for sex and has 2 principal pharmacologic actions in microcircuits: it is a full agonist at postsynaptic serotonin 5HT1A receptors and an antagonist at postsynaptic 5HT2A receptors.
lota-conotoxin RXIA is an agonist of voltage-gatedsodium channels (Nav1.2, 1.6, 1.7). Iota-conotoxin RXIAcan induce repetitive action potential and seizure in motor axons of frogsafter intracranial injection in mice [1].
Milnacipran-d5 (hydrochloride) is deuterium labeled Milnacipran (hydrochloride).
MT-7716 hydrochloride (W-212393 hydrochloride) is a selective non-peptide nociceptin receptor (NOP) agonist and promising potential treatment drug for alcohol abuse and relapse prevention[1].
Pantothenate kinase-IN-1 (Compound 1) is a pantothenate kinase (PANK) modulator with an IC50 of 0.51 µM against PANK3. Pantothenate kinase-IN-1 has a reasonable ligand efficiency (LipE = 2.8)[1].
TPA 023 is a GABAA α2/α3 subtype-selective agonist, with Ki of 0.19-0.41 nM.
Sodium Channel inhibitor1, one of 3-Oxoisoindoline-1-carboxamides, is a novel and selective voltage-gated sodium channel for pain treatment. IC50 Value: 0.16 uM ( Na v1.7, V hold-90mV); 0.41 uM (Na v1.7, V hold-90mV) [1]Target: Na v1.7Sodium Channel inhibitor1 demonstrated concentration-dependent efficacy in preclinical behavioral pain models.
GNE0877 is a highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitor with an IC50 of 3 nM.IC50 value: 3 nM [1]Target: LRRK2Invitrogen kinase-selectivity profiling(188 kinases) of aminopyrazole GNE0877 at 0.1 μM (145-fold overLRRK2 Ki) resulted in only four kinases showing greater than 50% inhibition (Aurora B = 51%, RSK2 = 52%, RSK4 = 62%, and RSK3 = 68%) and suggested that GNE0877 is a highly selective LRRK2 inhibitor. Furthermore, GNE0877 possessed a 212-fold biochemical-selectivity index over TTK (Ki= 150 nM), which was previously highlighted as an off-target kinase of concern because of the suggested role of TTK in themaintenance of chromosomal stability. The in vivo rat clearance for inhibitor GNE0877 was within 2-fold of measured in vitro stability, and good oral bioavailability (88%) was achieved at 50 mg/kg following administration of a methylcellulose/tween (MCT) suspension.
10,11-Dihydrocarbamazepine is the active metabolite of Oxcarbazepine. 10,11-Dihydrocarbamazepine also is an intermediate. Oxcarbazepine is rapidly and almost completely converted to 10,11-Dihydrocarbamazepine with probable Anticonvulsant efficacy[1].
M1/M4 muscarinic agonist 3 (compound 44) is a muscarinic mAChR M1/M4 agonist with EC50s of 31 nM and 9.3 nM, respectively[1].
MPEP hydrochloride is a potent and highly selective non-competitive antagonist at the mGlu5 receptor subtype with IC50 of 36 nM.IC50 Value: 36 nMTarget: mGluRin vitro: MPEP has no appreciable agonist or antagonist activity at the closely related recombinant human mGlu1b receptor expressed in CHO-K1 cells or a purinoreceptor endogenously expressed in L(tk-) cells up to concentrations of 100 μM. Furthermore, MPEP shows no appreciable agonist or antagonist activity in cAMP accumulation or [35S]-GTPγS binding assays at the recombinant human group II and III metabotropic receptors (human mGlu2, -3, -4a, -6, -7b, -8a) as well as the human NMDA (NMDAR1A/2A, -1A/2B), rat AMPA (GluR3) and human kainate (GluR6) receptor subtypes. In slices of rat neonatal hippocampus, striatum, and cortex but not cerebellum, MPEP inhibits DHPG-stimulated PI hydrolysis with IC50 of 8.0 nM, 20.5 nM, and 17.9 nM, respectively. MPEP positively modulates the hmGluR4 in a recombinant expression system, and the effect of MPEP is fully dependent on the activation of the orthosteric agonist L-AP4.in vivo: MPEP (1-30 mg/kg) induces anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MPEP (1-20 mg/kg) shortens the immobility time in a tail suspension test in mice, but it is inactive in the behavioural despair test in rats. MPEP has no effect on locomotor activity or motor coordination. MPEP significantly reduces fmr1 but not wild-type center square entries and duration. In open field tests, MPEP reduces fmr1tm1Cgr center field behavior to one indistinguishable from wild-type. MPEP produces a significant reduction of total locomotor activity in three of four groups tested, at both 10 mg/kg and 30 mg/kg.
ADX-47273 is a positive allosteric modulator selective for the metabotropic glutamate receptor subtype mGluR5(EC50=170 nM).IC50 value: 170 nM(EC50) [1] [2]Target: positive allosteric modulator (PAM) of mGluR5in vitro: ADX-47273 increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate [2]. in vivo: ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy [2]. ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning [3].
ML314 is a potent molecule agonist of NTR1 (EC50 = 1.9 μM); showed good selectivity against NTR2 and GPR35, but did not stimulate Ca2+ mobilization.IC50 value: 1.9 uM (EC50) [1]Target: NTR1 agonistMedicinal chemistry optimization of MLS-0233108 led to ML314, the most potent molecule in this second series that exhibited full agonist behavior (100 %) on NTR1 (EC50 = 1.9 μM). ML314 showed good selectivity against NTR2 and GPR35, but did not stimulate Ca2+ mobilization. ML314 is potentially a biased agonist operating via the β-arrestin pathway rather than the traditional Gq coupled pathway. Signaling mediated by β-arrestin has distinct biochemical and functional consequences that may lead to physiological advantages as described below. This probe report describes the discovery and properties of ML301 and summarizes the HTS and follow-up campaign, which identified ML314.