Delving into the Latest Updates on Landipirdine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Landipirdine (USAN/INN)

+ [5]

Target

5-HT2A receptor x 5-HT6 receptor

Action

antagonists

Mechanism

5-HT2A receptor antagonists(Serotonin 2a (5-HT2a) receptor antagonists), 5-HT6 receptor antagonists(Serotonin 6 (5-HT6) receptor antagonists)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Parkinson Disease

Inactive Indication

Cognition DisordersDementia due to Parkinson's disease

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization

F. Hoffmann-La Roche Ltd.

Inactive Organization

Acorda Therapeutics, Inc.Biotie Therapies Oy

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC18H19FN2O3S

InChIKeyMTTHRRVVGMPYQG-ZDUSSCGKSA-N

CAS Registry1000308-25-7

BACKGROUNDSYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms.OBJECTIVESWe evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD).METHODSIn a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI).RESULTSEighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028).CONCLUSIONSSYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study.REGISTRATIONClinicaltrials.gov as NCT02258152.

01 Dec 2022·Journal of NeuroinflammationQ1 · MEDICINE

Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease

Q1 · MEDICINE

ArticleOA

Author: Teunissen, Charlotte E ; Hoozemans, Jeroen J M ; Gombert, Iris ; Bubacco, Luigi ; van Eik, Jean-Marc ; Herrebout, Maaike A C ; Fayed, Mona M H E ; Pike, Adrianne F ; Varanita, Tatiana ; Faustini, Gaia ; Sandre, Michele ; Bellucci, Arianna ; Longhena, Francesca ; Veerhuis, Robert

AbstractBackgroundParkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1β (IL-1β), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models. Fibrillar α-syn activates this inflammasome in mouse and human macrophages, and we have shown previously that the same holds true for primary human microglia. Dopamine blocks microglial NLRP3 inflammasome activation in the MPTP model, but its effects in this framework, highly relevant to PD, remain unexplored in primary human microglia and in other in vivo parkinsonism models.MethodsBiochemical techniques including quantification of IL-1β secretion and confocal microscopy were employed to gain insight into dopamine signaling-mediated inhibition of the NLRP3 inflammasome mechanism in primary human microglia and the SYN120 transgenic mouse model. Dopamine and related metabolites were applied to human microglia together with various inflammasome activating stimuli. The involvement of the receptors through which these catecholamines were predicted to act were assessed with agonists in both species.ResultsWe show in primary human microglia that dopamine, l-DOPA, and high extracellular K+, but not norepinephrine and epinephrine, block canonical, non-canonical, and α-syn-mediated NLRP3 inflammasome-driven IL-1β secretion. This suggests that dopamine acts as an inflammasome inhibitor in human microglia. Accordingly, we provide evidence that dopamine exerts its inhibitory effect through dopamine receptor D1 and D2 (DRD1 and DRD2) signaling. We also show that aged mice transgenic for human C-terminally truncated (1–120) α-syn (SYN120 tg mice) display increased NLRP3 inflammasome activation in comparison to WT mice that is diminished upon DRD1 agonism.ConclusionsDopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K+. We suggest that dopamine serves as an endogenous repressor of the K+ efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology.

17 May 2017·ACS Chemical NeuroscienceQ3 · MEDICINE

Serotonergic Approaches in Parkinson’s Disease: Translational Perspectives, an Update

Q3 · MEDICINE

Review

Author: Fox, Susan H. ; Huot, Philippe ; Sgambato-Faure, Véronique ; McCreary, Andrew C.

Parkinson's disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of other neurotransmitters are affected by the disease process. One such neurotransmitter is serotonin (5-HT). 5-HT has been shown to play a role in several motor and nonmotor manifestations of PD, including tremor, cognition, depression and psychosis. 5-HT also seems to play a critical role in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. A breadth of preclinical studies and clinical trials have been conducted that aimed at modulating the 5-HT system in order to alleviate depression, cognitive deficits, psychosis, and dyskinesia. In this Review, we summarize recent advances in the 5-HT field in PD, but with a translational emphasis. We start by presenting a novel nonhuman primate model of PD that presents with dual dopamine and 5-HT lesions. We then present preclinical and clinical data that introduce new concepts, such as the use of biased and partial agonists, as well as molecules recently introduced to the field of PD, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, to enhance therapeutic benefit while minimizing adverse events, notably on parkinsonian disability.

100 Deals associated with Landipirdine

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External Link

KEGG	Wiki	ATC	Drug Bank
D11157	-	-	DB16214

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Dementia due to Parkinson's disease	Phase 1	United States	Acorda Therapeutics, Inc.	22 Dec 2014
Cognition Disorders	Preclinical	United States	Biotie Therapies Oy	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02258152 (SYNAPSE, CTgov)	Phase 2	Dementia due to Parkinson's disease	82	Placebo (Placebo)	bkzormtrxu(eihvxmkfje) = wvcapmlstj wokdzwroir (mqworayqmd, hmkwxnxgzi - wyqcvkfnct) View more	-	19 Apr 2019
				SYN120 (SYN120)	bkzormtrxu(eihvxmkfje) = icjdnykdtk wokdzwroir (mqworayqmd, ziwwoeencm - oerwogodih) View more
NCT02258152 (SYNAPSE, MDS2018)	Phase 2	Progressive Supranuclear Palsy Atypical	82	SYN120 100 mg daily	gzgaaqihha(duvkvklpkb) = incidence of nausea and vomiting were two-fold higher with SYN120 gtvcqimcfi (ywvroqmhvf ) View more	Negative	05 Oct 2018
				Placebo
MDS2018	Phase 2	Progressive Supranuclear Palsy Atypical	-	SYN120 100 mg daily	fqlbqpyyqf(kzwdwsaqcw) = Numerical improvements with SYN120 compared to placebo were also noted for SCOPA-SLEEP nighttime sleep (ES=0.47; p=0.05) lwzowfwufh (ofyoqowvui ) View more	-	05 Oct 2018
				Placebo