parkinson’s

MPTP hydrochloride is a precursor of MPP+, a dopamine neurotoxin with blood-brain barrier permeability. MPTP hydrochloride is toxic to dopaminergic neurons, which can lead to Parkinson's disease, and is widely used in the construction of animal models of Parkinson's disease.

5-Bromo-2’,3’,5’-tri-O-acetyluridine is a purine nucleoside analog that is being explored to improve Alzheimer’s and Parkinson’s diseases.

ST 1535 is a potent and orally active antagonist of A2A adenosine receptor with antiparkinsonian activity and antitremorigenic effects. ST 1535 exhibits the potential for the research of Parkinson’s disease.

SynuClean-D (SC-D) is an α-synuclein aggregation inhibitor preventing fibril propagation, disrupting mature amyloid fibrils, and abolishing the degeneration of dopaminergic neurons in an animal model of Parkinson’s disease.

BD-AcAc 2 (Ketone Ester) is a ketone monoester and can be used as a source of oral nutritional ketones. BD-AcAc 2 can elevate plasma levels of acetoacetate and β-hydroxybutyrate, blood Na+, blood glucose levels and blood creatinine levels after oral administration in mice. BD-AcAc 2 can partly prevent muscle weakness in septic mice. BD-AcAc 2 exhibits potential to improve endurance and exercise performance in animal body. BD-AcAc 2 can also be used to research diabetes or Parkinson’s disease.

Oxidopamine hydrochloride (6-Hydroxydopamine hydrochloride) is an neurotransmitter dopamine antagonist.

GYY4137 (GYY 4137 morpholine salt) is a novel water-soluble and slow releasing H2S donor with vasodilator and antihypertensive activity. GYY4137 also exhibits anti-inflammatory and anticancer activity.

Zonisamide (AD 810), a sulfonamide anticonvulsant, is approved for use as an adjunctive treatment in adults with partial-onset seizures. It may inhibit a carbonic anhydrase although this is not one of the main mechanisms of action. Zonisamide may act by blocking repetitive firing of voltage-gated sodium channels results in a reduction of T-type calcium channel currents, or by binding allosterically to GABA receptors. This latter action may lower the uptake of the inhibitory neurotransmitter GABA while increasing the uptake of the excitatory neurotransmitter glutamate.

1. Sinapine, an alkaloid from seeds of the cruciferous species, can be used as an effective natural compound for chemo-resistance. 2. Sinapine has antioxidant and radio-protective activities.

Oxidopamine hydrobromide (6-OHDA hydrobromide) is a neurotransmitter dopamine antagonist.

6-(1-Hydroxyethyl)-5,6-dihydrochelerythrine, an alkaloid, markedly alters the characteristics of cellular organelles—specifically, early endosomes, mitochondria, and autophagosomes—in Parkinson’s Disease patient-derived olfactory cells [1].

ELN484228 is a α-synuclein blocker. α-synuclein is a key protein in Parkinson’s disease.

Anhydrosafflor yellow B ((2S,3S)-6,7-dihydroxy-5-[(2E)-3-(4-hydroxyphenyl)prop-2-enoyl]-2-[(1S,2R,3R)-1,2,3,4-tetrahydroxybutyl]-3-{2,3,4-trihydroxy-5-[(2E)-3-(4-hydroxyphenyl)prop-2-enoyl]-6-oxo-3-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]cyclohexa-1,4-dien-1), isolated from Carthamus tinctorius, inhibits ADP-induced platelet aggregation, exhibits significant anti-oxidative effects in vitro, and possesses certain activity against H2O2-induced cytotoxicity.

Sinapine hydroxide, an alkaloid derived from the seeds of cruciferous plants, demonstrates a variety of beneficial properties including anti-inflammatory, anti-oxidant, anti-tumor, anti-angiogenic, and radio-protective effects. Additionally, it acts as an inhibitor of acetylcholinesterase (AChE), making it valuable for researching neurodegenerative conditions such as Alzheimer’s disease, ataxia, myasthenia gravis, and Parkinson’s disease[4].

Synucleozid hydrochloride is a potent the SNCA mRNA inhibitor that encodes α-synuclein protein (IC50=1.5 μM), has the potential for the investigation of Parkinson’s disease.

4A7C-301, a Nurr1 agonist, exhibits potent neuroprotective effects in vitro and markedly mitigates neuropathological abnormalities while enhancing motor and olfactory functions in male mouse models with AAV2-mediated α-synuclein overexpression. This compound is applicable in Parkinson’s disease research [1].

B2 (Linazolamide intermediate B impurity 2) promotes inclusion formation in cellular models of Huntington's disease and Parkinson's disease

XL01126, a potent degrader of LRRK2, exhibits DC50 values of 14 nM (G2019S LRRK2) and 32 nM (WT LRRK2), respectively. It has the ability to cross the blood-brain barrier, making it a viable degrader probe for Parkinson’s disease research. This compound is instrumental in exploring the non-catalytic and scaffolding functions of LRRK2 [1].

Valiglurax (VU2957), also known as VU0652957 and VU2957, is a potent, selective, CNS penetrant, and orally bioavailable mGlu4 PAM. VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson’s disease.

Diphenylpyraline hydrochloride (4-Diphenylmethoxy-1-methylpiperidine hydrochloride) is used in the treatment of Parkinsonism.It is a first-generation antihistamine with anticholinergic effects, functions as a dopamine reuptake inhibitor.

VU0410150, a pyrrylarylsulfone containing compound, has been found to be a mGluR4-positive allosteric modulator and has been evaluated as a potential drug for the treatment of Parkinson’s disease.

α-Synuclein inhibitor 8 effectively impedes α-Synuclein aggregation and disaggregation with an IC50 of 2.5 µM, demonstrating substantial reduction in neuronal inclusion formation, which contributes to reparative effects in damaged neurons and symptomatic improvement in Parkinson’s disease (PD)-like models. The compound also exhibits high antioxidant activity and low cytotoxicity [1].

α-Conotoxin PIA TFA, targeting nicotinic acetylcholine receptor (nAChR) subtypes with α6 and α3 subunits, acts as an antagonist. This compound shows promise for research into Parkinson’s disease and schizophrenia [1].

AMK is an active metabolite of the neurohormone melatonin .1,2,3,4It is formed from melatoninviathe metabolic intermediate AFMK that is then deformylated by catalase or formamidase.5,6AMK scavenges singlet oxygenin vitrowhen used at a concentration of 200 μM.1It inhibits the epinephrine- and arachidonic acid-induced production of prostaglandin E2and PGD2in ovine seminal vesicle microsomes in a concentration- and time-dependent manner, as well as LPS-induced increases in COX-2 levels in RAW 264.7 macrophages when used at a concentration of 500 μM.2,3AMK (20 mg/kg) decreases MPTP-induced increases in lipid peroxidation in the cytosol and mitochondria from substantia nigra and striatum in a mouse model of MPTP-induced Parkinson’s disease.4 1.Schaefer, M., and Hardeland, R.The melatonin metabolite N1-acetyl-5-methoxykynuramine is a potent singlet oxygen scavengerJ. Pineal Res.46(1)49-52(2009) 2.Kelly, R.W., Amato, F., and Seamark, R.F.N-acetyl-5-methoxy kynurenamine, a brain metabolite of melatonin, is a potent inhibitor of prostaglandin biosynthesisBiochem. Biophys. Res. Commun.121(1)372-379(1984) 3.Mayo, J.C., Sainz, R.M., Tan, D.-X., et al.Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophagesJ. Neuroimmunol.165(1-2)139-149(2005) 4.Tapias, V., Escames, G., López, L.C., et al.Melatonin and its brain metabolite N1-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian miceJ. Neurosci. Res.87(13)3002-3010(2009) 5.Tan, D.-X., Manchester, L.C., Reiter, R.J., et al.Melatonin directly scavenges hydrogen peroxide: A potentially new metabolic pathway of melatonin biotransformationFree Radic. Biol. Med.29(11)1177-1185(2000) 6.Hirata, F., Hayaishi, O., Tokuyama, T., et al.In vitro and in vivo formation of two new metabolites of melatoninJ. Biol. Chem.249(4)1311-1313(1974)

GOAT-IN-1 is an inhibitor of ghrelin O-acyltransferase (GOAT), which could be useful for the prophylaxis or treatment of diabetes, hyperlipidemia, non-alcoholic fatty liver, Alzheimer’s disease, Parkinson’s disease, cerebrovascular dementia, cerebral infa

(Rac)-BL-918 is the racemate of BL-918. BL-918 is a potent activator of UNC-51-like kinase 1 (ULK1) with an EC50 of 24.14 nM, inducing cytoprotective autophagy for Parkinson’s disease treatment [1].

Ibiglustat (L-Malic acid) (Ibiglustat L-Malic acid) is a selective, brain-penetrant, and allosteric inhibitor of glucosylceramide synthase. Ibiglustat (L-Malic acid) can be used in studies about PD Parkinson’s disease, SRT in Fabry’s and Gaucher’s.

NMDA receptor antagonist 2 is a highly potent and orally active NR2B subtype-selective antagonist of the N-methyl-D-aspartate (NMDA) receptor. It exhibits remarkable binding affinities, with an IC50 of 1.0 nM and a Ki value of 0.88 nM. This compound finds valuable application in scientific investigations focusing on neuropathic pain and Parkinson’s disease.

Dyrk1A-IN-3 (Compound 8b) is a highly selective inhibitor of dual-specificity tyrosine-regulated kinase 1A (DYRK1A). Dyrk1A-IN-3 has high binding affinity of DYRK1A with an IC 50 of 76 nM. Dyrk1A-IN-3 can be used in neurodegenerative disorders research, for example, Alzheimer’s Disease, Huntington’s Disease, and Parkinson’s Disease [1].

UCM-1306 is a potent and orally active allosteric modulator (PAM) of human dopamine D1 receptor. UCM-1306 could increase the maximal effect of endogenous dopamine (DA) both in human and mouse D1 receptors. UCM-1306 could improve motor symptoms and address the key comorbid cognitive impairment associated with long-term Parkinson’s disease (PD).

α-Synuclein 4554W, previously identified through intracellular library screening, is an inhibitor of α-Synuclein (aSyn) aggregation and its associated toxicity. This compound, comprising GIVNGVKA sequences, effectively reduces fibril formation in aSyn mutants associated with Parkinson’s disease [1].

Glucocerebrosidase-IN-1 (compound 11a) hydrochloride is a potent, selective GCase (glucocerebrosidase) inhibitor with IC50 and Ki values of 29.3 μM and 18.5 μM, respectively. It is utilized in the research of Gaucher disease (GD) and Parkinson’s disease (PD) [1].

HUP-55 is a prolyl endopeptidase inhibitor with an IC50 of 5 nM, shown to mitigate α-synuclein dimerization in Neuro2a cells, stimulate autophagy in HEK293 cells, and lower hydrogen peroxide-evoked reactive oxygen species (ROS) production in SH-SY5Y cells at a 10 µM concentration. Additionally, administration of HUP-55 at a dosage of 10 mg/kg reduces ipsilateral paw use and diminishes striatal oligomeric α-synuclein concentrations in a Parkinson’s disease mouse model, which is induced through adenoviral vector-mediated overexpression of α-synuclein (AAV-αSyn).

MAO-B-IN-15 is a selective inhibitor of MAO-B that forms π-π interaction with Tyr 326 residue (IC 50 = 13.5 μM) which can be used in Parkinson’s disease research[1].

Oxybuprocaine hydrochloride (Oxybuprocaine HCl), a local anesthetic, is used especially in otolaryngology and ophthalmology.

Neoechinulin C, an alkaloid in the echinulin class of indolediketopiperazine, shields neuronal cells from paraquat-induced damage in a Parkinson’s disease model [1].

Glucocerebrosidase-IN-1 (compound 11a) is a potent and selective GCase (glucocerebrosidase) inhibitor, with an IC 50 of 29.3 μM and a K i of 18.5 μM. Due to GCase involvement in pathological disorders consequent to enzyme deficiency, Glucocerebrosidase-IN-1 can be used for the research of Gaucher disease (GD) and Parkinson’s disease (PD)[1].

Monoamine Oxidase B inhibitor 2 is a potent, reversible, orally active and selective inhibitor of monoamine oxidase B (MAO-B) (IC50 = 1.33 nM) which can across the blood-brain barrier (BBB). Monoamine Oxidase B inhibitor 2 shows antioxidant and anti-neuroinflammatory activities which can be used in the study of Parkinson’s disease [1].

Sinapine Thiocyanate, is a derivative of Sinapine (S486605), an alkaloidal amine found in black mustard seeds. It is the choline ester of Sinapic Acid (S486800). It is also a phenolic-chloine conjugates, acting as anti-oxidants and acetylcholinesterase inhibitors, that can be used for the treatment of Alzheimer's disease (AD).

BL-918 is a potent activator of UNC-51-like kinase 1 (ULK1) with an EC50 of 24.14 nM.

ML-193 (CID 1261822) is a potent and selective GPR55 antagonist( IC50 : 221 nM). It shows more than 27-fold selectivity for GPR55 over GPR35, CB1 and CB2, and can improve the motor and the sensorimotor deficits of Parkinson’s disease (PD) rats.

hMAO-B/MB-COMT-IN-2 is a dual inhibitor of MAO-B/MB-COMT with IC 50s of 4.27 μΜ and 2.69 μΜ for hMAO-B and MB-COMT, respectively. hMAO-B/MB-COMT-IN-2 protects cells from oxidative damage that can be used in the neurodegeneration disease research, for example, Parkinson’s Disease (PD) [1].

MLi-2 is a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM).

Dityrosine, an oxidation product of protein formed through the intermolecular cross-linking of tyrosyl radicals from the reactive oxygen species (ROS) and tyrosine interaction, is associated with decreased hippocampal expression of NMDA receptor subunits Nr1, Nr2a, and Nr2b when administered intragastrically at 320 µg/kg per day, leading to memory impairments in mice as evidenced by their performance in a novel object recognition test. Additionally, it raises fasting blood glucose levels while reducing plasma insulin levels and the pancreatic expression of insulin synthesis-related genes Ins2, Pdx1, and MafA. Increased dityrosine levels have been positively linked to a range of diseases, including autism spectrum disorder, cataracts, Alzheimer’s disease, Parkinson’s disease, atherosclerosis, and cystic fibrosis.

YTX-465 is an inhibitor of both stearoyl-CoA desaturase(IC50s = 39 nM) and Ole1 (IC50s = 30.4 μM).

PBT434 methanesulfonate is an orally active, potent α-synuclein aggregation inhibitor with the ability to cross the blood-brain barrier. Acting as an iron chelator, it modulates transcellular iron trafficking, inhibits iron-mediated redox activity, and prevents iron-mediated aggregation of α-synuclein. PBT434 methanesulfonate also safeguards against the loss of substantia nigra pars compacta neurons (SNpc), showing promise for Parkinson’s disease (PD) research.

Auten-99 HBr (Auten-99) is a myotubularin phosphatase Jumpy inhibitor exerting potent neuroprotective effects. AUTEN-99 activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson’s and Huntington’s diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging.

MAO-B-IN-13 (compound 12a) is a highly potent, reversible and blood-brain barrier (BBB) penetrant MAO-B inhibitor (IC50 = 10 nM). MAO-B-IN-13 shows neuroprotective and antioxidant activity which can be used in Parkinson’s disease research [1].

DOPAL is an aldehyde product of the oxidative deamination of dopamine by monoamine oxidase.[1] It can be further oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase (ALDH) and, to a lesser extent reduced to 3,4-dihydroxyphenyl ethanol (DOPET). DOPAL is toxic to neurons.[2],[3] It can also oligomerize and precipitate α-synuclein, an event associated with Parkinson's disease.[2] Mice lacking cytosolic and mitochondrial forms of ALDH display increased levels of DOPAL as well as neurodegeneration and motor dysfunction characteristic of Parkinson’s disease.[4]

JH-II-127 is an orally inhibitor of leucine-rich repeat kinase 2 (LRRK2). It inhibits WT LRRK2, G2019S LRRK2 and A2016T LRRK2 (IC50s = 6.6, 2.2, and 47.7 nM, respectively),