GSK-2578215A is a potent and highly selective LRRK2 kinase inhibitor that possesses good blood-brain barrier (BBB) permeability with a high ratio of brain to plasma distribution in mice. GSK-2578215A was identified in a screen of GlaxoSmithKline’s KCS (a kinase-focused set of compounds for lead discovery) using a homogeneous time-resolved fluorescence (HTRF) assay that measured the inhibition of phosphorylation of the peptide substrate LRRKtide by baculoviral-derived recombinant 6His-Tev-LRRK2 (1326-2527). SAR and optimization of leads was performed using similar recombinant LRRK2 enzyme assays. GSK-2578215A exhibited biochemical IC50s of 10.9 and 8.9 nM against wild-type LRRK2 and LRRK2 [G2019S], respectively. The ability of GSK-2578215A to reduce phosphorylation levels of Ser910 and Ser935 in peripheral tissues on dosing to mice supports the notion that these phosphoepitopes can serve as markers of LRRK2 inhibitor activity in animal studies. Gene variants of the leucine-rich repeat kinase 2 (LRRK2) are associated with susceptibility to Parkinson's disease (PD). GSK-2578215A can be potentially used for the treatment of Parkinson's disease and other neurodegenerative diseases.

HU-210 is a synthetic cannabinoid. HU-210 is a highly potent cannabinoid receptor agonist. Also, it displays agonist activity at GPR55. HU-210 administration in adult rats results in a dose-dependent inhibition of plasma growth hormone, follicle stimulating hormone, and luteinizing hormone; modifications of plasma adrenocorticotropic hormone (ACTH) and corticosterone levels reveal a dose-dependent action on the pituitary-adrenal axis after acute exposure. HU-210 block beta-amyloid peptide-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. HU-210 induced a spatial deficit in the water maze in learning a reference memory task in numerous parameters together with alterations in hippocampal firing patterns of single principal neurons.

GBR-12935 (1-{2-benzhydryloxyethyl}-4-(3-phenylpropyl)piperazine) is a potent and selective inhibitor of dopamine transporter. Gist-Brocades originally initiated studies of GBR-12935 for the treatment of cocaine dependence. Tritium-labeled GBR-12935 may be used in radioligand binding studies. GBR-12935 is considered to be the metabolite of vanoxerine, another piperazine dopamine uptake inhibitor.

SCH-23390 is a potent and selective antagonist of the dopamine-1 and dopamine-5 receptors (Ki = 0.2 and 0.3 nM respectively). It was found to prevent death from d-amphetamine overdose in rats and has also been investigated as a potential treatment for Parkinson's Disease and Bipolar Disorder. A single clinical trial was conducted in healthy humans where SCH-23390 induced akathisia (motor restlessness). Preclinical and clinical trials as therapeutic have been discontinued due to side-effects and lack of efficacy. However, it should be noted that a C11 radiolabeled version of the compound has been synthesized and used as a PET imaging probe for the study of Parkinson's Disease and Huntington's Disease.

(-)-Sesamin is a lignan present in sesam oil and a number of medicinal plants. It exerts various pharmacological effects, such as prevention of hyperlipidemia, hypertension, and carcinogenesis. Moreover, (-)-sesamin has chemopreventive and anticancer activity in vitro and in vivo. (-)-Sesamin is an inhibitor of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. (-)-Sesamin is an antioxidant, showing effective 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity.

Isatin (1H-indole-2,3-dione) is a naturally occurring heterocycle that was first synthesised by Erdmann and Laurent in 1840. Isatin possesses a wide range of biological activities. Isatin has anxiogenic, sedative, anticonvulsant activities and acts as a potent antagonist on atrial natriuretic peptide receptors in vitro. Isatin is an endogenous monoamine oxidase (MAO) inhibitor involved in stress and anxiety. Additionally, isatin inhibits alkaline phosphatase (ALP), nitric oxide (NO)-stimulated soluble guanylate cyclase, and other enzymes.

Perlonguminine is an alkaloid amide isolated from species of the genus Piper, a plant used in traditional medicine that demonstrates antifungal, anticancer, antihyperlipidemic, and anti-inflammatory properties. Perlonguminine selectively targets a wide spectrum of cancer cells and induce cancer cell death by initiating various pathways, such as apoptosis, necrosis, and autophagy. The elevation of reactive oxygen species (ROS), characteristic of oxidative stress, is an important mechanism by which Perlonguminine promotes cancer-selective cell death. However, the poor aqueous solubility of Perlonguminine is a serious concern for intensive investigations and clinical application.

Norharman or beta-carboline (9H-pyrido[3,4-b]indole) is a neuroactive alkaloid first isolated from Peganum harmala L. It is implicated in a number of human diseases including Parkinson's disease, tremor, addiction and cancer. Norharman formed endogenously but external sources have been identified (among others fried meat and fish, meat extracts, alcoholic drinks, coffee brews, tobacco smoke). It inhibits monoamine oxidase and indoleamine 2,3-dioxygenase. In addition norharman binds with high affinity to imidazoline I2B receptors. Plasma norharman levels are elevated in chronic alcoholics and Parkinson's disease patients.

SKF-91488 is a noncompetitive inhibitor of histamine-N-methyltransferase. It modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo. SKF-91488 raised dose-dependently the pain threshold in rodent antinociception tests. Endogenous central histamine, after SKF 91488 treatment, via activation of H, receptors produces reversal of hypotension, with improvement in the survival rate at 2 h after treatment, in rats subjected to critical haemorrhagic hypovolaemia.

1-Phenyl-3-pyrazolidinone (phenidone) is a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX). Phenidone inhibits both the LO (lipoxygenase) and Cox (cyclooxygenase) pathways, the synthesis of Fos-related antigen protein, and is described as an anti-inflammatory and anti-oxidant compound. Phenidone is a potent hypotensive agent in the spontaneously hypertensive rat. Phenidone was also the best in suppressing LPS induced neurotoxicity, where the more potent neuroprotection by phenidone may be attributable to the synergistic effects of dual COX and LOX inhibition. Therefore, dual inhibitors of COX and LOX, such as phenidone, represent valuable candidates for the development of novel drugs for inflammation-related neurodegenerative disorders including PD.