Flupirtine Maleate(D 9998) is a selective neuronal potassium channel opener that also has NMDA receptor antagonist properties.IC50 Value: Target: Potassium channel; NMDA receptorin vitro: High concentrations of flupirtine antagonized inward currents to NMDA(200 microM) at -70 mV with an lC50 against steady-state responses of 182.1+/-12.1 microM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine [1]. Therapeutic flupirtine concentrations (≤10 μM) did not affect voltage-gated Na(+) or Ca(2+) channels, inward rectifier K(+) channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of K(V)7 K(+) channels to more negative potentials and the gating of GABA(A) receptors to lower GABA concentrations [2]. Cell exposure to flupirtine decreased the amplitude of delayed rectifier K(+) current (I(K(DR))) with a concomitant raise in current inactivation in NSC-34 neuronal cells [4].in vivo: Rats were trained to discriminate the novel analgesic flupirtine (10.0 mg/kg i.p., 10 min) from no drug under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.87 mg/kg. The opioid analgesics pentazocine, codeine and tramadol failed to produce flupirtine appropriate responding. The opioid antagonist naltrexone did not antagonize the discriminative effects of flupirtine [3]. Both morphine (ED50=0.74 mg/kg) and flupirtine (ED50=3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation [5]. Toxicity: Based on study-end data, hepatotoxicity was detected in 31% of patients receiving flupirtine for ≥ 6 weeks [6].
Pardoprunox hydrochloride is a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist, D2 (pKi = 8.1) and D3 receptor (pKi = 8.6) partial agonist and 5-HT1A receptor (pKi = 8.5) full agonist.IC50 value: 8.1/8.6/8.5 (pKi, for D2/ D3/5-HT1A receptor)Target: dopamine D2 and D3 receptor, 5-HT1A receptorin vitro: Pardoprunox also binds to D4 (pKi = 7.8), α1-adrenergic (pKi = 7.8), α2-adrenergic (pKi = 7.4), and 5-HT7 receptors (pKi = 7.2) with lower affinity. Pardoprunox acts as a potent but partial D(2) receptor agonist (pEC50 = 8.0 and pA2 = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D3 receptors, Pardoprunox acts as a partial agonist in the induction of [35S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [35S]GTPgammaS binding (pA2 = 9.0). Pardoprunox acts as a full 5-HT1A receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT1A receptors but with low potency (pEC50 = 6.3) [1].in vivo: Pardoprunox induces contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In MPTP-treated common marmosets, Pardoprunox dose-dependently increases locomotor activity (MED=0.03mg/kg; po) and decreases motor disability (MED=0.03mg/kg; po). In contrast Pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induces 5-HT1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po). Collectively, these findings demonstrate that Pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional D2 receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD.[2]
CS587 is a specific inhibitor of CaMK1D with neurocytotoxicity at 10 μM. CS587 modulates the sensitivity of neuronal cells to Aβ oligomer toxicity[1].
Pipamperone (Floropipamide; McN-JR 3345; R 3345) is a high-affinity antagonist of 5-HT2A receptor (pKi=8.2) and D4 receptor (pKi=8.0) and a low-affinity antagonist of D2 receptor (pKi=6.7)[1].
(+)-Dihydrexidine hydrochloride is a dopamine D1 receptor agonist with an EC50 of 72± 21 nM.
SHR1653 is a highly potent, selective and brain penetrated oxytocin receptor (OTR) antagonist, with an IC50 of 15 nM for hOTR[1].
Bopindolol ((±)-Bopindolol) malonate is an orally active antagonist of β-adrenoceptors (ARs) with partial agonist activity. Bopindolol malonate is non-selective for β1- and β2-ARs and has low affinity for β3-AR subtype. Bopindolol malonate has intrinsic sympathomimetic as well as membrane stabilizing actions, inhibits renin secretion, and interacts with 5-HT receptors. Bopindolol malonate is a prodrug of Pindolol (HY-B0982). Bopindolol malonate can be used for essential and renovascular hypertension research[1][2][3][4].
Neuropeptide SF (mouse,rat) is a potent neuropeptide FF receptor agonist with Ki values are 48.4 nM and 12.1 nM for NPFF1 and NPFF2, respectively. Neuropeptide SF increases the amplitude of the sustained current of heterologously expressed acid sensing ion channel 3 (ASIC3) [1].
Adrenochrome (Adraxone) is an oxidation product of Epinephrine. Adrenochrome is a potent coronary constricting agent in the rat heart. Adrenochrome can be used for neurological disorder research[1][2][3].
Secretin (33-59), rat is a 27-aa peptide, acts on secretin receptor, enhances the secretion of bicarbonate, enzymes, and K+ from the pancreas.
Riluzole is an anticonvulsant drug and belongs to the family of use-dependent Na+ channel blocker which can also inhibit GABA uptake with an IC50 of 43 μM.
(R)-(-)-O-Desmethyl Venlafaxine D6 is the deuterium labeled (R)-(-)-O-Desmethyl Venlafaxine. O-Desmethyl Venlafaxine is an active metabolite of Venlafaxine[1]. Venlafaxine (HY-B0196) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class[2].
SCH 39166 hydrobromide (SCH391660) is potent and selective antagonist of dopamine D1/D5 receptor, with Kis of 1.2 nM and 2.0 nM, respectively. SCH 39166 hydrobromide shows more than 40-flod selectivity over D2, D4, 5-HT, and α2a receptor (Ki=0.98, 5.52, 0.08, and 0.73 μM, respectively). SCH 39166 hydrobromide can be used for the research of schizophrenia, cocaine addition, and obesity[1].
Picroside II, an iridoid compound extracted from Picrorhiza, exhibits anti-inflammatory and anti-apoptotic activities. picroside II alleviates the inflammatory response in sepsis and enhances immune function by inhibiting the activation of NLRP3 inflammasome and NF-κB pathways[1]. Picroside II is an antioxidant, exhibits a significant neuroprotective effect through reducing ROS production and protects the blood-brain barrier (BBB) after cerebral ischemia-reperfusion (CI/R) injury[2].
MTIC-d3 is deuterium labeled MTIC. MTIC is the active metabolite of Temozolomide (TMZ). MITC has lower bioavailability in the brain compared with TMZ, because the drug’s permeability through biological barriers and tumor cell membranes affects bioavailability. MITC exhibits low affinity to biological membrane[1].
Levemopamil hydrochloride is a blood-brain barrier penetrable calcium channel blocker and a 5-HT2 antagonist. Levemopamil hydrochloride can be used for temporary occlusion and neurological disease research[1].
Duloxetine is a serotonin-norepinephrine reuptake inhibitor with Ki of 4.6 nM, used for treatment of major depressive disorder and generalized anxiety disorder (GAD). Target: SNRIsDuloxetine inhibits the reuptake of serotonin and norepinephrine in the central nervous system. Duloxetine is also considered a less potent inhibitor of dopamine reuptake. However, duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NA transporters. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity. Major depressive disorder is believed to be due in part to an increase in pro-inflammatory cytokines within the central nervous system. Antidepressants including ones with a similar mechanism of action as duloxetine, i.e. serotonin metabolism inhibition, cause a decrease in proinflammatory cytokine activity and an increase in anti-inflammatory cytokines; this mechanism may apply to duloxetine in its effect on depression but research on cytokines specific to duloxetine therapy is lacking [1]. The analgesic properties of duloxetine in the treatment of diabetic neuropathy and central pain syndromes such as fibromyalgia are believed to be due to sodium ion channel blockade [2].
(R)-PQ-912 is a glutaminyl cyclase (QC) inhibitor extracted from patent WO2011029920A1, example 13, has an IC50 of 30.2 μM and a Ki of 7.25 μM for hQC[1].
AAK1-IN-3, a quinoline analogue, is a brain-penetrant adaptor protein 2-associated kinase 1 (AAK1) inhibitor with an IC50 of 11 nM. AAK1-IN-3 has the potential for neuropathic pain research[1].
Rufinamide(E 2080; CGP 33101; RUF 331) is a new antiepileptic agent that differs structurally from other antiepileptic drugs and is approved as adjunctive therapy for Lennox-Gastaut syndrome (LGS).IC50 Value:Target: in vitro:in vivo: Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline) in mice [1]. Oral rufinamide suppressed pentylenetetrazol-induced seizures in mice (ED(50) 45.8 mg/kg) but not rats, and was active against MES-induced tonic seizures in mice (ED(50) 23.9 mg/kg) and rats (ED(50) 6.1 mg/kg) [2]. Intraperitoneal rufinamide suppressed pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED(50) 54.0, 50.5, and 76.3 mg/kg, respectively).Clinical trial: Exploratory Study to Evaluate the Effect of SYN-111 (Rufinamide) in Patients With Generalized Anxiety Disorder (GAD). Phase 2
SUN13837 is an orally active, potent and BBB-penetrated FGFR (fibroblast growth factor receptor) modulator. SUN13837 shows neuroprotective activity. SUN13837 can be used for neurodegenerative diseases research[1].
2-Hydroxyalbrassitriol (Compound 6) is an AChE inhibitor with an IC50 of 35.97 μM[1].
MCAAD-3 is a near-infrared Aβ imaging probe with blood-brain barrier penetrability. MCAAD-3 has a strong affinity for Aβ polymers (Ki >106 nM) and can label Aβ plaques in the brains of transgenic mice[1].
Valorphin is an endogenous hemoglobin β-chain (33-39) fragment with opioid analgesic activity, binds to rat mu-opioid receptor, with an IC50 of 14 nM; Valorphin also shows anti-tumor activity.
Dehydroaripiprazole-d8-1 is the deuterium labeled Dehydroaripiprazole. Dehydroaripiprazole (OPC-14857) is an active metabolite of Aripiprazole. Aripiprazole is an antipsychotic agent and is metabolized by CYP3A4 and CYP2D6 forming mainly Dehydroaripiprazole. Dehydroaripiprazole has with antipsychotic activity equivalent to Aripiprazole[1] [2] [3] [4] .
Org-10490 is an antagonist of dopamine D1 receptor and dopamine D2 receptor, used for the treatment for psychiatric disease.
Melatonin is a hormone made by the pineal gland that can activates melatonin receptor. Melatonin plays a role in sleep and possesses important antioxidative and anti-inflammatory properties.
SGC-CK2-1 is a highly potent, ATP-competitive, and cell-active CK2 chemical probe with exclusive selectivity for both human CK2 isoforms, with IC50s of 36 and 16 nM for CK2α and CK2α′respectively in the nanoBRET assay. SGC-CK2-1 can be used for the research of neurodegenerative diseases[1][2].
Pardoprunox(SLV-308) is a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist; D2 (pKi = 8.1) and D3 receptor (pKi = 8.6) partial agonist (IA = 50% and 67%, respectively) and 5-HT1A receptor (pKi = 8.5) full agonist (IA = 100%); also binds to D4 (pKi = 7.8), α1-adrenergic (pKi = 7.8), α2-adrenergic (pKi = 7.4), and 5-HT7 receptors (pKi = 7.2) with lower affinity.IC50 value:Target:in vitro: SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3) [1].in vivo: Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; -7.3 points), as compared with placebo (-3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (> or = 30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001) [2]. Surprisingly in the SNc, pardoprunox (10 μg kg?1, i.v.) either partially or fully suppressed the firing activity in two separate populations of DA neurons. Finally, in the DRN, pardoprunox (5-40 μg kg-1, i.v.) completely suppressed the firing activity of 5-HT neurons. Moreover, the selective 5-HT(1A) receptor antagonist WAY-100,635 prevented and reversed the effects of pardoprunox [3].
Ritanserin (R 55667) is a highly potent, relatively selective, orally active, long acting antagonist of 5-HT2 receptor, with an IC50 of 0.9 nM, less active on Histamine H1, Dopamine D2, Adrenergic α1, Adrenergic α2 receptors[1].